The neuropoietic cytokine family in development, plasticity, disease

Transkript

REVIEWS
The neuropoietic cytokine family in
development, plasticity, disease
and injury
Sylvian Bauer*||, Bradley J. Kerr‡|| and Paul H. Patterson§
Abstract | Neuropoietic cytokines are well known for their role in the control of neuronal,
glial and immune responses to injury or disease. Since this discovery, it has emerged that
several of these proteins are also involved in nervous system development, in particular
in the regulation of neurogenesis and stem cell fate. Recent data indicate that these
proteins have yet more functions, as key modulators of synaptic plasticity and of various
behaviours. In addition, neuropoietic cytokines might be a factor in the aetiology of
psychiatric disorders.
Stem cell self-renewal
A characteristic of stem cells,
which divide asymmetrically to
give rise to a new stem cell
(self-renewal) and a more
differentiated progenitor cell.
Tissue stem cells can thereby
persist in the long term and
ensure a continuous supply of
more differentiated
progenitors.
*Physiologie
Neurovégétative, UMR 6153
CNRS, 1147 INRA, Université
Paul Cézanne-Aix-Marseille-3,
Ave. Escadrille NormandieNiemen, BP 351-352, 13397
Marseille Cedex 20, France.
‡
Department of
Anesthesiology and Pain
Medicine, University of
Alberta, Edmonton, Canada.
§
Biology Division, California
Institute of Technology,
Pasadena, California, USA.
Correspondence to P.H.P.
e-mail: [email protected]
||
These authors contributed
equally to this work
doi:10.1038/nrn2054
Cytokines are small proteins that were first characterized as components of the immune response, but have
since been found to play a much broader part in diverse
aspects of physiology. They signal through a gp130 receptor complex that activates the Janus-activated kinase–
signal transducer, activator of transcription (JAK–STAT)
and mitogen-activated protein kinase (MAPK) signal
transduction pathways (FIG. 1).
The group of structurally related cytokines consisting
of interleukin-6 (IL-6), IL-11, IL-27, leukaemia inhibitory
factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), neuropoietin and cardiotrophin-like
cytokine (CLC; also known as novel neurotrophin 1
(NNT1) and B cell stimulating factor 3 (BSF3)) has been
given various names, including the IL-6 family (after
its ‘founding member’), the gp130 family (because all
members signal through the gp130 receptor) and the
neuropoietic family (for its effects on haematopoietic
and nervous systems). In this article, we refer to these
proteins as the neuropoietic family.
In addition to their well-known involvement in infection, pregnancy, and bone, muscle and cardiovascular
function, these cytokines have recently been shown
to have signalling functions in the normal developing
and adult brain, and in the response to brain injury and
disease. So, these proteins are central to many brain
processes. This review evaluates the vital role of neuropoietic cytokines during nervous system development
and in the coordination of neuronal, glial and immune
responses to injury and disease, and discusses the emerging data regarding their roles in synaptic plasticity and
behaviour.
NATURE REVIEWS | NEUROSCIENCE
Control of neural stem and progenitor cell fate
Self-renewal of neural stem cells. In early development as well as in the adult, stem cell self-renewal
ensures a continuous supply of newly differentiated
cells that populate various organs and tissues. In mice,
LIF is well known for its role during development in
promoting totipotent embryonic stem cell (ESC) selfrenewal1 (FIG. 2) through activation of the JAK–STAT
pathway2. In humans, LIF does not support in vitro
ESC self-renewal3, but is required for the long-term
growth of embryonic human neural stem cells (NSCs)4,5.
However, these cells still undergo replicative senescence
after prolonged in vitro culture, indicating that they
are actually neural progenitors with a limited self-renewing capacity6. In addition, LIF might alter human NSC
differentiation, as it promotes neurogenesis in stem
and progenitor cells derived from the adult human
olfactory bulb7,8.
The mechanisms underlying self-renewal, proliferation and differentiation of NSCs have been primarily
studied with the neurosphere assay, an in vitro technique that has provided important insights into these
processes9,10. Experiments performed using this technique indicated that LIF signalling promotes the maintenance and self-renewal of mouse embryonic NSCs
in vitro. Indeed, dissociated cells from LIF receptor
(Lifr)-knockout mice generate fewer secondary neurospheres than cells taken from wild-type mice11,12, indicating a reduction in self-renewal capacity. Conversely,
exogenous LIF promotes secondary sphere formation
from wild-type cells11,13, that is, it expands the number
of sphere-forming cells. Similar results were obtained
VOLUME 8 | MARCH 2007 | 221
© 2007 Nature Publishing Group
REVIEWS
Embryonic stem cell
(ESC). A particular type of stem
cell that is derived in vitro from
the inner cell mass of the early
embryo at the blastocyst stage.
ESCs are totipotent, that is,
they can give rise to any
differentiated cell type.
Neural stem cell
(NSC). A self-renewing stem
cell of the neural lineage, that
is, it can give rise to neurons,
astrocytes and
oligodendrocytes.
Replicative senescence
Stage at which cells maintained
in vitro cease proliferation and
cannot be passaged further.
Neural progenitor cell
Dividing cell that has a limited
proliferating and self-renewing
capacity, and is restricted to
the neural lineage.
with exogenous CNTF12 acting through activation of
the Notch signalling pathway14, an essential component
for the maintenance of NSCs15.
Interestingly, endogenous LIF is secreted by neurospheres16, indicating that, in vitro at least, the effect of
LIF on NSC self-renewal occurs through an autocrine/
paracrine mechanism. Further in vitro evidence indicates
that this stimulatory action of LIF and CNTF on NSC
self-renewal and maintenance might be limited to certain regions of the nervous system, because in contrast to
cells derived from the forebrain, neither LIF nor CTNF
seem to promote self-renewal in cells isolated from the
embryonic spinal cord13.
Some of the neurosphere assay findings are supported
by in vivo experiments in mice which showed that gp130
regulates cell cycle re-entry of embryonic cortical progenitors, and that this is stimulated by exogenous LIF17.
Developmental switch from neurogenesis to gliogenesis.
It is known that, during brain development, neurogenesis
occurs before gliogenesis; however, the precise molecular events underpinning the timing of this are not fully
understood. In vitro evidence indicates that cell-intrinsic
mechanisms have a role in determining this switch
because these timed events can be mimicked in clones
of embryonic cortical NSCs18. It has also been suggested
that extrinsic signals could be involved, and particular
attention has been paid to CNTF and LIF. LIF has been
known for some time to have a role in determining
cell phenotype and was originally characterized in the
nervous system for its ability to induce a switch from
a noradrenergic to a cholinergic phenotype in cultured
sympathetic neurons19. LIF and CTNF induce premature
generation of astrocytes in vitro through activation of the
gp130–gp130
LIFR–gp130
IL-6
LIF
CNTF
OSMR–gp130
CT-1
OSM
gp130
OSMR
?
gp130
LIFR
LIFR
CNTFR
gp130
gp130
LIFR
IL-6R
gp130
Cell membrane
gp130
Extracellular
Intracellular
Activation of
JAK–STAT and
MAPK pathways
Figure 1 | Neuropoietic cytokine receptor complexes. Various combinations of
receptor subunits and signalling pathways are used by different members of the
neuropoietic cytokine family. gp130 homodimers associate with specific interleukin (IL)
receptors such as the IL-6 receptor (IL-6R) to mediate the actions of IL-6. Leukaemia
inhibitory factor (LIF) binds to heterodimers of LIF receptor (LIFR) and gp130. LIFR–gp130
heterodimers can also associate with other receptor subunits to bind ciliary neurotrophic
factor (CNTF) and cardiotrophin 1 (CT-1). The oncostatin M receptor (OSMR) forms
heterodimers with gp130 to bind oncostatin M (OSM). The signal-transducing subunit
gp130 is found in all complexes, and is responsible for the intracellular activation of the
Janus-activated kinase–signal transducer and activator of transcription (JAK–STAT) and
the mitogen-activated protein kinase (MAPK) pathways. Modified, with permission, from
REF. 177 © (2003) Portland.
222 | MARCH 2007 | VOLUME 8
JAK–STAT and MAPK pathways16,20. Interestingly, LIF
mediates astrogliogenesis in late (>E15), but not early
(E12–E14), cortical progenitors in mice16,21. This could
be due to a developmental increase in expression of the
epidermal growth factor receptor (EGFR)22, which synergizes with LIF signalling to induce astrocyte differentiation23. In addition, cytokine-induced STAT signalling
directly activates the expression of various members of
the JAK–STAT pathway in a positive, auto-regulatory
fashion 24, leading to a potentiation of JAK–STATinduced astrocyte development over time.
In vivo, extrinsic and intrinsic mechanisms also have
a role in the sequential generation of neurons and glial
cells during development. It has been suggested that LIF,
synthesized prenatally by neural progenitors, might act in
an autocrine/paracrine manner16. However, other studies have presented evidence that Lif and Cntf expression
commence only postnatally21,25. In Lif- or Cntf-knockout
mice, cortical gliogenesis seems to occur normally21, and
adult astrocyte numbers are reduced only in discrete
areas such as the hippocampus, in Lif-knockout mice26,27.
By contrast, mice lacking gp130 or its co-receptor LIFR
exhibit a marked deficit in astrocyte formation26,28,29. So,
although knocking out individual cytokines does not
produce a phenotype that is notably different from wild
type, blocking the action of the entire cytokine family
reveals its crucial role in gliogenesis in vivo.
These data also indicate that, in single knockout
animals, redundancy within the cytokine family or
activation of compensatory mechanisms might occur,
as has been described for motor neuron survival30,31.
Importantly, another family member, CT-1, is synthesized by developing neurons and accumulates in the
extracellular space, where it triggers the switch from
neuronal to astrocyte fate after most neurons have been
generated21. Consistent with this finding, CT-1-knockout
mice exhibit a strong deficit in cortical gliogenesis21.
So, LIF or CNTF alone do not seem to be necessary
for embryonic gliogenesis, whereas CT-1 is crucial for
the proper timing of the switch from neurogenesis to
gliogenesis.
Neural stem cells versus astrocytes. As noted above,
neuropoietic cytokines, particularly LIF and CTNF,
play an important part in the differentiation of astrocytes
from neural progenitors in vitro. Indeed, studies using
the neurosphere assay have indicated that LIF signalling promotes astrocyte-like cell formation, measured by
an increased expression of glial fibrillary acidic protein
(GFAP)11,32–34. These observations might seem paradoxical considering that LIF and CNTF also promote
the maintenance of NSCs11–13. In fact, the Gfap gene is
neuropoietic cytokine-responsive, as its promoter region
contains STAT recognition sequences24. Furthermore, it
has been well demonstrated that a subpopulation of Gfapexpressing cells remains neurogenic within neurospheres
and in the adult brain35,36. Experiments also indicate that
CNTF inhibits glial cell fate restriction in uncommitted
neurosphere cells, resulting in the maintenance of the
NSC phenotype in these cells, while accelerating
the differentiation of progenitors already committed to
www.nature.com/reviews/neuro
REVIEWS
LIF?
CNTF
Self-renewal
Inhibition
Development
CNTF
Cell fate
GFAP+
astrocytes
LIF
?
Totipotent
embryonic
stem cells
CNTF
LIF
CNTF?
?
Primitive neural
stem cells
LIF
CNTF
LIF
CNTF
GFAP+ neural
stem cells
Oligodendrocytes
LIF
IL-6
CNTF
Neurons
Figure 2 | LIF and CNTF regulation of stem cells: from totipotent embryonic stem
cells to adult neural stem cells. Leukaemia inhibitory factor (LIF) supports the selfrenewal of mouse totipotent embryonic stem cells, and might be involved in the
generation of primitive neural stem cells, whose self-renewal in the early embryo is under
the control of unknown factors. Later in development, LIF and possibly ciliary
neurotrophic factor (CNTF) induce glial fibrillary acidic protein (Gfap) expression in cells
that retain the cardinal properties of neural stem cells, including self-renewal and
multipotentiality. Self-renewal of mature, Gfap-positive (GFAP+) neural stem cells is
promoted by LIF and CNTF. Whereas CNTF inhibits the restriction of multipotent neural
stem cells to the glial lineage, both LIF and CNTF promote astrocyte differentiation.
In vivo, LIF, as well as interleukin-6 (IL-6), reduces neurogenesis, whereas CNTF promotes
neurogenesis. LIF and CNTF also promote the maturation and survival of
oligodendrocytes.
Subventricular zone
(SVZ). Area lining the lateral
ventricle, which contains neural
stem and progenitor cells that
give rise to new neurons in the
olfactory bulb of the adult
brain.
the astrocytic lineage12. Altogether, these data indicate
that some GFAP-positive, astrocyte-like cells self-renew
and generate both neurons and glial cells, whereas others
are differentiated astrocytes (FIG. 2). So, GFAP is not a
lineage-specific marker in the context of NSCs.
An important quality of the neurosphere assay is that
cells can be exposed to different conditions independently. Culturing neurosphere cells in the presence of
bone morphogenetic proteins (BMPs), another gliogenic
cytokine family, induces astrocyte differentiation in vitro,
similar to the effects of LIF or CNTF. Importantly, however, the Gfap-expressing cells generated in the presence
of BMPs differ in morphology and phenotype from
Gfap-expressing cells induced by LIF34. LIF-treated cells,
for example, exhibit a bipolar, elongated radial morphology, a feature also observed for Gfap-expressing adult
NSCs in vivo36, whereas those treated with BMPs have
a stellate morphology, which is a characteristic of differentiated astrocytes. LIF-treated NSCs also express the
radial glial marker vimentin, which is absent in those
treated with BMPs34. In addition, neurosphere cell proliferation continues in the presence of LIF but is strongly
inhibited by BMPs, and multipotent neurospheres can
be obtained efficiently from Gfap-expressing cells generated in the presence of LIF, but not in the presence
of BMPs34. So, although LIF induces Gfap expression in
cultured neural stem and progenitor cells, these cells do
not terminally differentiate into astrocytes but rather
retain the cardinal characteristics of NSCs, again indicating that Gfap expression is not lineage-specific. Overall,
these in vitro results indicate that neuropoietic cytokines
such as LIF are important for initiating Gfap expression
but not astrocyte cell fate determination (FIG. 2), and that
different cytokines induce differentiation into cells with
specific morphologies and, presumably, functions.
Adult NSC self-renewal and differentiation. It is now
well accepted that neurogenesis also occurs in certain
parts of the adult brain, and it has recently emerged
that, in addition to influencing NSC self-renewal and
differentiation in the developing animal, neuropoietic
cytokines perform similar functions in the adult. For
example, infusion of CNTF into the brains of wild-type
adult mice increases the number of subventricular zone
(SVZ)-derived neurospheres generated from these
mice, indicating that exogenous CNTF can increase the
number of neural stem and progenitor cells in this brain
area12. CNTF administration also stimulates neurogenesis in the adult hippocampus37 and the hypothalamus38
in vivo. It is possible that exogenous CNTF promotes
proliferation and survival of progenitor cells, as well as
neuronal migration37.
Intracerebroventricular injection of anti-CNTF antibodies in wild-type mice inhibits SVZ cell proliferation,
indicating that endogenous CNTF regulates adult neurogenesis in vivo37. However, it remains unclear whether
LIF or CNTF regulates the balance between adult NSCs
and more committed progenitors in vivo.
Adult Lifr+/– mice exhibit reduced cell proliferation
in the SVZ and decreased neurogenesis in the olfactory
bulb compared with wild-type mice. In addition, the
number of sphere-forming cells derived from the SVZ
of these mice is reduced compared with wild-type mice,
indicating a depletion of NSCs in this area12 and highlighting the key role of LIF signalling in the self-renewal
and maintenance of adult NSCs.
Further insight into the effects of LIF on adult NSCs
and neurogenesis in vivo is provided by adenovirusmediated overexpression of Lif in the lateral ventricle of
adult mice, which results in a reduction of neurogenesis
in the SVZ and olfactory bulb39. These results are similar
to those obtained using transgenic Il-6 overexpression
in vivo, which reduces adult hippocampal neurogenesis40.
Further analyses of SVZ cell dynamics in animals treated
with exogenous LIF revealed that LIF differentially
modulates the self-renewing properties of various SVZ
cell types: whereas LIF decreases the self-renewal of early
neuronal progenitors such as the transit amplifying cells,
also called type C cells41, it promotes the amplification
of NSCs39.
Interestingly, whereas the number of SVZ-derived
neurospheres obtained from adult Lifr+/– mice is reduced
compared with those obtained from wild-type mice, no
difference is observed in those obtained from early postnatal (P0) Lifr+/– and wild-type animals12. This indicates
that LIF and CNTF are necessary for NSC self-renewal
REVIEWS
Autoregenerative factor
Factor synthesized by a
population of degenerating
cells that promotes the
regeneration of the same cell
type.
specifically in the adult brain, whereas they seem to be
dispensable in this function during development. Instead,
other factors could regulate the maintenance of NSCs
during development in vivo. In addition, embryonic and
adult NSCs might respond differently to similar cues. It
is notable that, unlike adult NSCs, early embryonic NSCs
do not express Gfap42, indicating the possibility that LIF
and CNTF become necessary for NSC self-renewal only
when NSCs start expressing Gfap. Interestingly, adult
Lif-knockout mice exhibit a reduction in GFAP-positive
cells in the hippocampus26,27, in which NSCs are known
to express Gfap43. This observation might therefore
reflect a deficit in NSC number and self-renewal in adult
mice devoid of LIF.
In summary, LIF stimulates the self-renewal and
maintenance of adult NSCs in vivo, similar to its effect
on mouse ESCs and embryonic NSCs in vitro, indicating
that LIF could be useful in promoting regeneration from
endogenous stem and progenitor cells in the injured adult
nervous system. These results also indicate that LIF and
CNTF have differential effects on adult neurogenesis,
the former being inhibitory whereas the latter is stimulatory. Such a duality of effect could result from the fact
that CNTF might not impair further amplification of
progenitor cells beyond the NSC stage, as LIF does39.
Furthermore, it should be noted that any cell that responds
to CNTF could also respond to LIF. Therefore, differences
or specificities in cytokine actions are likely to rely on the
expression of CNTF receptor subunit-α (FIG. 1).
Cytokines in the injured nervous system
Injury-induced neurogenesis. An understanding of the
factors controlling neurogenesis and differentiation
in both the developing and adult brain is vital for the
development of therapeutic strategies aimed at repairing the CNS following injury. Certain signals produced
by the injured brain seem to activate endogenous repair
mechanisms. Although cell regeneration in the injured
adult nervous system is limited, the enhancement or
modulation of repair processes by exogenous substances
such as growth factors and cytokines could offer hope
for new therapies.
Two types of endogenous signals produced by the
injured brain seem to be involved in brain repair: factors
synthesized by dying cells, and inflammation-related
cytokines. It has been demonstrated that localized and
synchronous apoptosis of adult cortical neurons leads
to an induction of neurogenesis in the neocortex, with
the re-appearance of new corticothalamic or corticospinal projection neurons44,45. In these experiments, the
induction of neurogenesis occurs without an obvious
inflammatory reaction, indicating that signals released
by dying neurons might be promoting neurogenesis.
Furthermore, in vitro studies show that diffusible, heatlabile factors from the adult apoptotic cortex stimulate
the growth of SVZ neurospheres through enhanced
cell proliferation, whereas conditioned medium from a
healthy cortex is inhibitory46.
Lif expression is very low in the nervous system
under normal physiological conditions, but it is rapidly
and transiently increased following various types of
injuries, including trauma, seizure and ischaemia47–53.
In a study showing that LIF is necessary for the induction of progenitor cell proliferation in the injured
adult olfactory epithelium, we found that LIF is synthesized in part by dying olfactory sensory neurons49.
So, in this model, LIF seems to be an autoregenerative
factor, stimulating the replacement of dying neurons.
However, it seems that endogenous LIF might be primarily involved in lesion-specific reactions, at least in
some brain areas, because lack of LIF does not cause a
deficit in progenitor cell proliferation in the olfactory
epithelium of non-lesioned animals49. Given that exogenous LIF promotes NSC self-renewal in the normal,
adult SVZ39, and that most injuries that upregulate LIF
expression also stimulate SVZ- or hippocampal cell
proliferation, it is possible that LIF could be broadly
involved in the recruitment of NSCs and progenitor
cells after injury, which probably constitutes the first
step towards regeneration.
There is increasing evidence that LIF might also modulate neurogenesis after injury in the context of inflammation. LIF is synthesized by infiltrating macrophages
at later timepoints after olfactory bulbectomy54,55, as
well as by astrocytes and occasionally by microglial cells
following cortical injury or hippocampal seizures47,50.
Chronically overexpressed Lif in the uninjured adult
brain activates astrocytes and microglia, and reduces
neurogenesis in the SVZ/olfactory bulb system39. CNS
inflammation is detrimental for adult hippocampal
neurogenesis; although it does not alter precursor cell
proliferation, it reduces neuronal differentiation and/or
survival56,57. These negative effects on differentiation
and survival are due, at least in vitro, to microgliaderived IL-6 (REF. 56), and in vivo, neurogenesis can be
restored by anti-inflammatory treatments that inhibit
microglial activation56,57. These findings have potential
clinical relevance.
In animal models of stroke, neurogenesis is induced in
the adult striatum, probably resulting from an activation
of both endogenous NSCs and more committed progenitors in the SVZ; however, very few newly generated neurons survive in the long-term58–60. Hypoxia–ischaemia
performed in postnatal animals also stimulates SVZ cell
proliferation and increases the number of cells that form
neurospheres in vitro61. These events correlate with an
induction of Lif, gp130 and Notch1 expression61, indicating that LIF signalling could regulate the recruitment
of NSCs and progenitor cells after hypoxia–ischaemia
or stroke. Inflammation might, at longer timepoints,
be responsible for the low number of surviving new
neurons; indeed, anti-inflammatory treatment increases
post-stroke neurogenesis62,63. In addition, exogenous LIF
can rescue neurons subjected to ischaemia64. Therefore,
LIF can both increase proliferation in certain brain areas
and enhance neuron survival under certain conditions,
thereby facilitating recovery.
Neurotrophic and regenerative actions. As discussed
above, neuropoietic cytokines modulate a variety of
injury responses in the PNS and CNS. In vivo, LIF
regulates the expression of various neuropeptides such as
REVIEWS
Macrophage
Monocyte
Galanin/VIP
NPY
Injured
axons
Axons
Regenerating
axon
Schwann
cell
+
LIF
+ MCP1
Peripheral sensory ganglion
Figure 3 | LIF mediates injury responses in the PNS. In normal peripheral sensory
ganglia the expression of various neuropeptides such as vasoactive intestinal peptide
(VIP) and galanin are constitutively low. Cut or crush injuries to the axons of these cells
lead to a rapid induction of leukaemia inhibitory factor (LIF), primarily by Schwann cells.
LIF can act back on the Schwann cells in an autocrine and paracrine manner to promote
their survival. Increased production of LIF might also lead to the enhanced expression
of other pro-inflammatory chemotactic factors such as monocyte chemoattractant
protein 1 (MCP1; also known as CCL2) that assist in the recruitment of monocytes and
macrophages into the degenerating nerve. LIF is also retrogradely transported back to
the sensory neurons where it is responsible for the induction of VIP (in the superior
cervical ganglion (SCG)) and galanin (in the dorsal root ganglion). Exogenous delivery of
LIF leads to increased expression of substance P in the SCG. LIF is also important for the
induction of neuropeptide Y (NPY) in the injured ganglia, but this effect seems to be
restricted to small diameter sensory neurons.
galanin, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and substance P (SP) in peripheral sympathetic and sensory neurons following injury65,66, as well
as in the hippocampus following seizure67. These changes
in neuropeptide expression might represent a mechanism by which LIF exerts its reparative actions (FIG. 3).
It has been proposed that neuropeptides might enhance
neuronal survival through their neurotrophic actions.
They might also act as chemotactic agents for immune
cells, or alter the balance of electrical activity in the brain
so as to resist further seizures or other abnormal circuit
activity. Inactivation of the gp130 receptor also reveals a
requirement for the neuropoietic cytokine family in the
noradrenergic–cholinergic switch that occurs normally
in vivo in a subpopulation of sympathetic neurons innervating the sweat glands, where cholinergic transmission
is required for gland function68.
Nerve injury induces an upregulation of many neuropoietic cytokines. For example, LIF is upregulated rapidly after peripheral nerve injury, primarily in Schwann
cells48. A similar upregulation of oncostatin M (OSM),
IL-6 and IL-11 also occurs, with variations in the degree
and duration of expression after injury69,70. Interestingly,
unlike the other members of the neuropoietic cytokine
family, Cntf is highly expressed in normal nerves71,
and peripheral nerve injury typically downregulates its
expression70,72. There is increased retrograde transport
of LIF and CNTF in sensory and motor neurons after
sciatic nerve injury73–75, and a mechanism for anterograde transport of LIF to deafferentiated muscle has
been described76.
Il-6, CNTF and LIF are critical survival factors for several types of neurons during development and following
injury in adulthood77–79. For example, axotomy-induced
Il-6 expression in sensory neurons can upregulate brainderived neurotrophic factor in adult rodents80, indicating
that the trophic effect of IL-6 might be indirect in this
case. By contrast, LIF can directly promote the survival
of cultured neural crest-derived sensory neurons81 as
well as embryonic spinal motor neurons82. However, the
viability of motor neuron populations in vivo seems to
be only mildly affected in Lif-knockout mice, indicating
that other factors might be involved30. LIF and CTNF
seem to be primarily responsible for promoting the
survival and maintenance of developing motor neurons
postnatally30,77, although deletion of the Cntf gene has
more pronounced effects than Lif gene deletion on this
cell type30,83.
Exogenous LIF, CNTF and IL-6 can each effectively
rescue facial and spinal motor neurons after axotomy
performed in the first postnatal week, a period when
these cells are highly susceptible to axotomy-induced
cell death83–85. These cytokines are also effective in
promoting motor neuron survival in animal models of
virally induced injury86 and motor neuron disease87,88.
These observations prompted optimism that CNTF
and LIF might represent novel therapeutic agents for
neurodegenerative disorders such as amyotrophic lateral
sclerosis (ALS)89. However, the success of these compounds in animal models of ALS has been mixed90–92,
and in a human clinical trial CNTF provided little benefit
and caused unwanted side effects93. Similarly, following
promising results in animal models, LIF was tested in a
clinical trial for the prevention of chemotherapy-induced
peripheral neuropathy, with negative results94. Owing to
its success in animal models, clinical trials of CNTF in
Huntington’s disease are underway95.
CT-1, unlike CNTF, LIF and IL-6, has the characteristics of a target-derived trophic factor, being expressed
at high levels by skeletal muscle during embryonic
development96. CT-1 seems to have a different role from
other neuropoietic cytokines: it functions primarily to
support embryonic motor neuron survival, without any
apparent effects on peripheral nerve injury in adulthood97. However, systemic administration of CT-1 can
slow disease progression in an adult mouse model of
spinal muscular atrophy98. In addition, analysis of triple
Lif/Cntf/CT-1-knockout mice reveals a significant loss
of spinal cord motor neurons, which is accompanied by
behavioural impairments31. This study also highlights
the crucial role of endogenous LIF in the maintenance
of distal axons and motor endplates, which cannot be
compensated for by endogenous CNTF or CT-1 (REF. 31).
LIF and IL-6 are important factors for axonal regeneration in the PNS and CNS. Exogenous Lif and Il-6
overexpression promote the regeneration of lesioned
peripheral nerves99–101. Conversely, Lif- and Il-6-knockout
mice exhibit impaired regeneration after peripheral
nerve lesion100,102. In addition, LIF and IL-6 are important factors for the ‘conditioning lesion’ effect, whereby
the growth status of a sensory neuron is potentiated
after an injury to its peripheral branch103,104. In the CNS,
REVIEWS
Normal
Myelin
Oligodendrocyte
Motor
neuron
Axon
b Autoimmune
a Axotomy
c Spinal cord injury
encephalomyelitis
T cell
LIF
CNTF
IL-6
Apoptosis
LIF
T-cell destruction
of myelin and
oligodendrocytes
LIF
Loss of myelin and
oligodendrocytes
Figure 4 | Neuropoietic cytokines promote motor neuron and oligodendrocyte survival after injury or disease.
a | Axotomy in the early postnatal period leads to a significant loss of motor neurons from apoptotic cell death. Exogenous
delivery of the neuropoietic cytokines leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) or interleukin-6
(IL-6) significantly attenuates this apoptosis. Exogenous delivery of these cytokines is also effective at limiting apoptosis in
animal models of motor neuron disease. b | LIF is also effective at promoting oligodendrocyte survival. In experimental
autoimmune encephalomyelitis (EAE), there is a significant T-cell-mediated loss of oligodendrocytes and myelin.
Administration of LIF is effective at limiting the loss of myelin and oligodendrocytes. c | There is also a considerable loss of
oligodendrocytes and myelin following spinal cord injury. Treatment with LIF after spinal cord injury is accompanied by
greater myelin preservation and fewer apoptotic oligodendrocytes.
the transplantation of fibroblasts that overexpress Lif
enhances corticospinal tract regeneration after spinal
hemisection105, and intrathecal infusion of IL-6 promotes
regeneration of lesioned dorsal column axons104. By contrast, retinal ganglion cell survival following axotomy is
increased in Il-6-knockout mice106. This indicates that
the role of IL-6 is skewed towards its ability to stimulate
pro-inflammatory signalling cascades after optic nerve
injury, and away from its trophic and regenerative effects
in other systems.
Oligodendrocytes and autoimmune demyelinating disorders. In addition to their trophic actions on sensory
and motor neurons, neuropoietic cytokines promote
the maturation and survival of oligodendrocytes, the
myelinating cells of the CNS107. LIF, CNTF and IL-6
each promote the survival of mature oligodendrocytes
in culture, and delivery of CNTF to the developing optic
nerve enhances oligodendrocyte survival in vivo107,108. A
recent study also showed that LIF, released by astrocytes
in response to ATP stimulation, promotes the myelination of developing axons109. Upregulation of Lif, Cntf
and Il-6 expression is observed in patients with multiple sclerosis110,111 and in experimental autoimmune
encephalomyelitis (EAE), an animal model of autoimmune demyelination112. Il-6 expression in multiple
sclerosis is found primarily in inactive lesions and is correlated with axonal sparing at these sites110. When EAE
is induced in Cntf-knockout mice or in the presence of
anti-LIF antibodies, there is enhanced severity of clinical
symptoms, and increased demyelination, axonal injury,
and oligodendrocyte death112,113. Therefore, the upregulation of Lif, Cntf and Il-6 in multiple sclerosis could
reflect an endogenous protective mechanism against
axonal injury and oligodendrocyte death. In addition,
exogenous LIF promotes oligodendrocyte survival and
myelin sparing in EAE114 (FIG. 4), although this treatment
strategy seems to be ineffective in another autoimmune
demyelinating paradigm, experimental autoimmune
neuritis115. Interestingly, conditionally knocking-out
a negative regulator of gp130–LIFR signalling —
suppressor of cytokine signalling 3 (SOCS3) — protects
against cuprizone-induced loss of oligodendrocytes
and myelin116, highlighting the importance of LIFR
activation in promoting oligodendrocyte survival after
injury. Although mutations in Lif and Cntf genes do not
seem to be associated with the development of multiple
sclerosis 117,118, patients with this disease who carry a null
REVIEWS
Gliosis
The process of producing a
dense fibrous network of
neuroglia; includes astrocytosis
— the proliferation of
astrocytes in the area of a
degenerative lesion.
Mechanical allodynia
Pain caused by a mechanical
stimulus that is normally
perceived as non-painful.
Thermal hyperalgesia
An increased sensitivity to a
painful thermal stimulus.
Neuropathic pain
Pain initiated or caused by a
primary lesion or dysfunction
of the nervous system.
C-fibre
The small diameter,
unmyelinated axons of sensory
neurons that convey
information about potentially
tissue-damaging stimuli.
mutation in Cntf show signs of a more rapid onset and
increased severity of the disease119. Although conflicting data from clinical populations exist in this regard119,
these observations have been corroborated in the EAE
animal model113.
Similar roles for neuropoietic cytokines have been
suggested in models of spinal cord injury (FIG. 4), in
which exogenous LIF reduces oligodendrocyte apoptosis
and promotes functional recovery, with greater numbers
of myelinated axons120,121. By striking contrast, intrathecal infusion of IL-6 can cause demyelination in the spinal
cord, and conflicting results have been obtained for IL-6
in various models of EAE122. Taken together, LIF and
CNTF seem to hold the greatest potential for development as therapeutic agents for demyelinating disorders
such as multiple sclerosis, or after CNS injuries that are
accompanied by extensive oligodendrocyte apoptosis.
Regulation of inflammatory and nociceptive responses.
LIF, CNTF and IL-6 are key activators of astrocytes and
microglia in the CNS response to injury. Indeed, Lif-,
Cntf- or Il-6-knockout mice show diminished astrocyte
and microglia reactivity in a variety of injury models123–
126
. The response of the attenuated astrocytes following
mechanical injury to the cortex in Il-6-knockout mice is
correlated with delayed wound healing and prolonged
breakdown of the blood–brain barrier. Conversely,
overexpression of Il-6 in Gfap–Il-6 transgenic mice
increases the rate of wound healing126. However, when
Lif or Il-6 are overexpressed in the spinal cord of noninjured mice, astrocyte and microglial activation are
dramatically enhanced127,128, resulting in severe motor
impairments127. Following spinal cord injury, these
mice exhibit significantly increased lesion sizes and
decreased axonal growth128. These findings illustrate
the importance of ascertaining the appropriate doses for
exogenous administration of these cytokines, as elevating LIF or IL-6 above a particular threshold can lead to
gliosis, inflammation and an adverse outcome.
The neuropoietic cytokine family is also linked to
inflammation and pain following injury. In contrast
to its role within the nervous system, LIF acts as an antiinflammatory cytokine during cutaneous inflammation.
The Freunds complete adjuvant paradigm is a classical
model of inflammatory pain and results in mechanical
allodynia and thermal hyperalgesia . Endogenous LIF
negatively regulates the expression of pro-inflammatory
mediators such as IL-1β and nerve growth factor, and
administration of LIF delays the onset of and diminishes
mechanical allodynia and thermal hyperalgesia in this
model129. By contrast, in the absence of inflammation,
injection of high doses of LIF in the skin can promote the
development of mechanical allodynia129,130. Interestingly,
in the injured peripheral nerve, LIF is distinctly proinflammatory. Although absence of LIF in the skin leads
to a significant increase in immune cell infiltration after
injury129, this infiltration was significantly impaired in
the injured sciatic nerve of Lif-knockout mice124. In addition, LIF, unlike IL-6, is chemotactic for macrophages
in vitro124, and can regulate the expression of other
macrophage chemoattractants such as the chemokine
monocyte chemoattractant protein 1 (MCP1; also
known as CCL2)131. These findings indicate a complex
role for LIF in pain processing. Its pro-inflammatory
actions within the nervous system might promote hyperalgesia and facilitate neuropathic pain. By contrast, its
anti-inflammatory actions in cutaneous tissue indicate
an important role for LIF in regulating and diminishing
peripheral inflammatory hyperalgesia.
In addition to LIF, IL-6 and OSM play a part in
nociception. Indeed, receptors for these cytokines are
expressed by sensory neurons in the dorsal root ganglion132,133. Osm-knockout mice show a significant reduction of neurons that co-express the vanilloid receptor
transient receptor potential vanilloid 1 (TRPV1) and
the ionotropic purinoreceptor P2X3 (REF. 134), which
are important for transducing signals for noxious heat
and inflammatory stimuli. The diminished expression
of these channels might underlie the blunted responses
to noxious thermal, mechanical and chemical stimuli in
these mice134. The effects of IL-6 on nociceptive processing are more complex. While intracerebroventricular or
intrathecal administration of IL-6 causes behavioural
hyperalgesia in normal and nerve-injured animals135,136,
exogenous IL-6 can also depress C-fibre responses and
diminish the hyperexcitability of spinal projection
neurons after spinal nerve ligation137. Conflicting reports
on the basal sensitivity to noxious thermal and mechanical processing in the absence of injury have also been
reported in Il-6-knockout mice102,138,139. However, there is
consensus that neuropathic pain behaviours after partial
sciatic nerve injury are attenuated in these mice140, indicating an overall pro-nociceptive role for this cytokine
after peripheral nerve injury.
Maternal infection and mental illness. Activation of the
maternal immune system by respiratory infection can
affect fetal brain development and the behaviour of adult
offspring. Similarly, activation of the maternal immune
response by artificial methods, such as by injection of
synthetic dsRNA (polyI:C) to mimic a viral infection, can
also affect fetal brain development. These effects on the
developing brain have significant consequences in adulthood such as a greater predisposition to certain types of
mental illness. For example, respiratory infection and
elevated cytokine levels in pregnant women significantly
raise the risk of schizophrenia in the offspring141. Animal
experiments indicate that increased IL-6 in the maternal
serum has a key role in this association. Indeed, many of
the effects of maternal immune activation on the fetus
can be prevented by blocking IL-6. For example, maternal
injection of poly(I:C) during pregnancy yields offspring
with adulthood deficits in social interaction, latent inhibition and open field behaviour, and also in prepulse
inhibition of the acoustic startle response, a measure of
sensorimotor gating that is deficient in schizophrenia142.
These behavioural deficits are blocked by co-injection of
anti-IL-6 antibody. Injection during pregnancy of IL-6
causes deficits in prepulse inhibition, latent inhibition
and spatial learning in adult offspring143 (S. Smith, J. Li and
P.H.P., unpublished observations). Thus, elevated
maternal IL-6 levels have profound effects on the fetal
REVIEWS
brain — possibly directly, by crossing the placenta and
entering the fetal brain, or indirectly, by acting on the
placenta or other fetal membranes or organs. Localizing
the signalling pathways that are activated by IL-6 at
both tissue and cellular levels will reveal where prenatal
IL-6 effects occur. It might also be useful to study LIF
in this context, given its vital importance in embryo
implantation and early development.
Synaptic plasticity and behaviour
Long-term potentiation. So far, we have discussed the
roles of neuropoietic cytokines during development,
and how many of these pathways and mechanisms
are reactivated following CNS injury. However, it has
recently been demonstrated that in normal, healthy
adult animals, neuropoietic cytokines are produced by
CNS neurons in a variety of physiological paradigms.
For example, IL-6 can directly affect neuronal activity
and is implicated in long-term potentiation (LTP) (for a
review, see REF. 144). Indeed, following LTP induction,
Il-6 expression is upregulated in hippocampal astrocytes and in cells in nearby blood vessels, raising the
possibility of a role for haematopoietic elements in LTP
induction or maintenance145. Mice overexpressing Il-6 in
astrocytes exhibit deficits in LTP146, but they also show
severe pathology in the hippocampus and cerebellum,
which might account for these deficits147. This model of
long-term Il-6 overexpression might not be optimal for
assessing the role of the endogenous cytokine in synaptic plasticity, but the application of relatively low levels
of exogenous IL-6 to hippocampal slices also reduces
LTP148,149. Moreover, injection of anti-IL-6 antibodies
causes a remarkable prolongation in LTP, as well as
an improvement in long-term memory150, indicating a
potentially significant role for IL-6 in this process. A role
for IL-6 in learning and memory is further supported by
other cognitive tests. Il-6-knockout mice perform better
than wild-type mice in passive avoidance and radial arm
maze tasks of learning, both in terms of acquisition and
retention151. Conversely, Il-6 overexpression or hippocampal injection of IL-6 impairs retention in avoidance
learning tests152,153.
Although the mechanism by which IL-6 alters activity, synaptic plasticity and learning remains to be determined, potential insight is gained from studies showing
that chronic elevation of IL-6 in vivo or in vitro alters the
physiological properties of Purkinje cells, reducing their
firing rate and decreasing current-evoked spike activity154. This could be through direct action on neurons
and through the regulation of Ca2+ influx144. In addition,
endogenous IL-6 reduces susceptibility to seizure induction155 and Il-6 overexpression enhances the sensitivity
to NMDA (N-methyl-d-aspartate)-induced seizures156,
further supporting the notion that IL-6 could regulate
neuronal excitability.
Stress, feeding, sleep and depressive behaviours. Neuropoietic cytokines are involved in mediating various
behaviours, including those related to feeding, sleep
and stress. Clc is expressed with a circadian rhythm
in SCN neurons, and regulates daily motor activity157.
Alterations in IL-6 levels also affect sleep as well as
body temperature, which is consistent with the extensive literature on cytokine involvement in sickness
behaviour158,159,160. Furthermore, there is evidence that
Il-6-knockout mice exhibit increased aggressive behaviour, whereas Il-6 overexpression enhances affiliative
social interactions161. These effects on social interaction
seem to be robust, and warrant further exploration.
Stress, inflammation and infection upregulate IL-6
and LIF and activate the hypothalamic–pituitary–adrenal
(HPA) axis to maintain physiological homeostasis. LIF,
along with corticotropin-releasing hormone (CRH),
enhances pro-opiomelanocortin expression and
adrenocorticotropin secretion162, which are indicative
of a physiological stress response. Further supporting a
role for LIF in HPA axis regulation, Lif-knockout mice
exhibit an attenuated adrenocorticotropin response during restraint stress. Furthermore, exogenous IL-6 induces
Crh expression in amygdala neurons, which are involved
in the regulation of emotional and stress-associated
behaviours. However, there are conflicting reports as to
whether Il-6-knockout mice exhibit altered behaviour
in models of anxiety such as the elevated plus maze and
open field stress tests144,163,164.
Perhaps also relevant to stress is the finding that
central administration of IL-6 or LIF induces fatigue,
asthenia and anorexia. In addition, there are now many
reports that patients exhibiting these symptoms during
major depression or bipolar disorder have elevated serum
IL-6 levels, and that antidepressant drugs lower IL-6
levels165–170. Moreover, Lif-knockout mice show reduced
immobility in the forced swim test171 — a test of depressivelike behaviour and response to antidepressant drugs
— but other reports show conflicting results158,172.
Lif and Lifr are expressed in hypothalamic nuclei that
are sites of production, release and action of neuropeptides implicated in the control of feeding behaviour and
energy expenditure173. Indeed, central administration
of LIF reduces weight gain, food intake and adiposity,
and suppresses levels of leptin, a neuropeptide with a
well-characterized role in feeding behaviour. Because
Lif-knockout mice also exhibit decreased body weight,
a critical window for LIF levels seems to be necessary for
weight control174. The situation for IL-6 seems to be more
complex: human fat secretes substantial levels of IL-6, and
plasma levels are highly correlated with body mass and
inversely correlated with insulin sensitivity175. However,
central administration of IL-6 in rodents increases energy
expenditure and decreases body fat, and Il-6-knockout
mice are said to develop obesity associated with glucose
intolerance. Central, but not peripheral, replacement
of IL-6 in these mice partially reverses the obesity175,
although several of these findings have not been confirmed164. There are also reports of IL-6 involvement
in cancer cachexia (loss of weight) and exercise endurance164. Thus, the situation for IL-6 is less clear than for
LIF, and it might be that IL-6 acts differentially at central
and peripheral levels to affect the above behaviours.
The similarity of the signalling pathways associated
with the neuropoietic cytokine family and those associated with leptin have inspired a direct comparison of
REVIEWS
the effects of leptin, LIF and CNTF on feeding behaviour. The proteins were overexpressed in rat brains by
central injection of viral vectors176. Leptin, Lif and Cntf
overexpression caused similar but not identical changes
in body weight and eating behaviour. Moreover, most of
the changes in hypothalamic gene expression induced by
leptin overexpression were also seen when Cntf and/or Lif
were overexpressed. Some of these changes in hypothalamic gene expression are characteristic of chronic
inflammation. It is interesting that CNTF injection into
the cerebrospinal fluid causes weight loss that persists
beyond the time of treatment173; this is not the case with
other weight loss regimens. It was recently reported that
CNTF administration induced neurogenesis in the feeding centres of the mouse hypothalamus, and blocking this
effect with cytosine arabinoside abrogated the long-term
but not the short-term effect of CNTF on body weight38.
These findings open up a series of fascinating questions
in relation to the use of the neuropoietic cytokine family
as dietary drugs, and possible neurogenesis in brain areas
involved in the regulation of feeding behaviour and its
control by these cytokines.
Clinical implications and future research
It is clear that neuropoietic cytokines are key regulators of NSC proliferation and differentiation. Given
their roles in controlling neuronal, glial and immune
1.
Williams, R. L. et al. Myeloid leukaemia inhibitory
factor maintains the developmental potential of
embryonic stem cells. Nature 336, 684–687 (1988).
2.
Burdon, T., Smith, A. & Savatier, P. Signalling, cell
cycle and pluripotency in embryonic stem cells.
Trends Cell Biol. 12, 432–438 (2002).
3.
Thomson, J. A. et al. Embryonic stem cell lines derived
from human blastocysts. Science 282, 1145–1147
(1998).
4.
Carpenter, M. K. et al. In vitro expansion of a
multipotent population of human neural progenitor
cells. Exp. Neurol. 158, 265–278 (1999).
5.
Wright, L. S. et al. Gene expression in human neural
stem cells: effects of leukemia inhibitory factor.
J. Neurochem. 86, 179–195 (2003).
6.
Wright, L. S., Prowse, K. R., Wallace, K., Linskens, M. H.
& Svendsen, C. N. Human progenitor cells isolated
from the developing cortex undergo decreased
neurogenesis and eventual senescence following
expansion in vitro. Exp. Cell Res. 312, 2107–2120
(2006).
7.
Galli, R., Pagano, S. F., Gritti, A. & Vescovi, A. L.
Regulation of neuronal differentiation in human CNS
stem cell progeny by leukemia inhibitory factor.
Dev. Neurosci. 22, 86–95 (2000).
8.
Pagano, S. F. et al. Isolation and characterization of
neural stem cells from the adult human olfactory bulb.
Stem Cells 18, 295–300 (2000).
9.
Reynolds, B. A. & Weiss, S. Generation of neurons and
astrocytes from isolated cells of the adult mammalian
central nervous system. Science 255, 1707–1710
(1992).
10. Seaberg, R. M. & van der Kooy, D. Adult rodent
neurogenic regions: the ventricular subependyma
contains neural stem cells, but the dentate gyrus
contains restricted progenitors. J. Neurosci. 22,
1784–1793 (2002).
11. Pitman, M. et al. LIF receptor signaling modulates
neural stem cell renewal. Mol. Cell. Neurosci. 27,
255–266 (2004).
12. Shimazaki, T., Shingo, T. & Weiss, S. The ciliary
neurotrophic factor/leukemia inhibitory factor/gp130
receptor complex operates in the maintenance of
mammalian forebrain neural stem cells. J. Neurosci.
21, 7642–7653 (2001).
Shows that LIF signalling is crucial for the
maintenance of NSCs in vitro.
cell responses in various disease and injury paradigms,
these cytokines could also influence cell replacement
through NSCs, in natural as well as therapeutic settings.
The ability of LIF to increase the population of NSCs in
adulthood indicates possible applications to brain injury
or neurodegenerative disease; harnessing endogenous
NSCs would have many potential advantages over stem
cell transplantation.
The regulation of NSCs could be one way through
which neuropoietic cytokines influence behaviour and
higher CNS functions, as in the case of feeding behaviour. Furthermore, neuropoietic cytokines modulate
neuronal excitability as well as glial and immune cell
function, providing another route by which they could
affect behaviour. For example, these factors converge in
the experience of, and response to, pain.
Some of the most promising clinical prospects for
neuropoietic cytokines seem to be their protective actions
on oligodendrocytes. Particularly striking are their effects
in animal models of multiple sclerosis, in which peripheral
injection of LIF or CNTF can ameliorate symptoms112–114.
However, given the pleiotropy of these cytokines, a
significant hurdle for their therapeutic use is that doses
need to be established that will not, for example, adversely
affect body weight or induce detrimental inflammatory
responses. Localized delivery, such as with viral gene
therapy and inducible vectors, may be required.
13. Gregg, C. & Weiss, S. CNTF/LIF/gp130 receptor
complex signaling maintains a VZ precursor
differentiation gradient in the developing ventral
forebrain. Development 132, 565–578 (2005).
14. Chojnacki, A., Shimazaki, T., Gregg, C., Weinmaster, G.
& Weiss, S. Glycoprotein 130 signaling regulates
Notch1 expression and activation in the self-renewal
of mammalian forebrain neural stem cells. J. Neurosci.
23, 1730–1741 (2003).
15. Hitoshi, S. et al. Notch pathway molecules are
essential for the maintenance, but not the generation,
of mammalian neural stem cells. Genes Dev. 16,
846–858 (2002).
16. Chang, M. Y., Park, C. H., Son, H., Lee, Y. S. & Lee, S. H.
Developmental stage-dependent self-regulation of
embryonic cortical precursor cell survival and
differentiation by leukemia inhibitory factor. Cell Death
Differ. 11, 985–996 (2004).
17. Hatta, T., Moriyama, K., Nakashima, K., Taga, T. &
Otani, H. The role of gp130 in cerebral cortical
development: in vivo functional analysis in a mouse
exo utero system. J. Neurosci. 22, 5516–5524 (2002).
18. Qian, X. et al. Timing of CNS cell generation: a
programmed sequence of neuron and glial cell
production from isolated murine cortical stem cells.
Neuron 28, 69–80 (2000).
19. Yamamori, T. et al. The cholinergic neuronal
differentiation factor from heart cells is identical to
leukemia inhibitory factor. Science 246, 1412–1416
(1989).
20. Bonni, A. et al. Regulation of gliogenesis in the central
nervous system by the JAK–STAT signaling pathway.
Science 278, 477–483 (1997).
21. Barnabe-Heider, F. et al. Evidence that embryonic
neurons regulate the onset of cortical gliogenesis via
cardiotrophin-1. Neuron 48, 253–265 (2005).
Shows that although neither LIF nor CNTF are
required for the proper timing of the
developmental switch from neurogenesis to
gliogenesis, CT-1 is crucial.
22. Burrows, R. C., Wancio, D., Levitt, P. & Lillien, L.
Response diversity and the timing of progenitor cell
maturation are regulated by developmental changes in
EGFR expression in the cortex. Neuron 19, 251–267
(1997).
23. Viti, J., Feathers, A., Phillips, J. & Lillien, L. Epidermal
growth factor receptors control competence to
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
interpret leukemia inhibitory factor as an astrocyte
inducer in developing cortex. J. Neurosci. 23,
3385–3393 (2003).
He, F. et al. A positive autoregulatory loop of Jak–
STAT signaling controls the onset of
astrogliogenesis. Nature Neurosci. 8, 616–625
(2005).
Stockli, K. A. et al. Regional distribution,
developmental changes, and cellular localization of
CNTF-mRNA and protein in the rat brain. J. Cell Biol.
115, 447–459 (1991).
Koblar, S. A. et al. Neural precursor differentiation
into astrocytes requires signaling through the
leukemia inhibitory factor receptor. Proc. Natl Acad.
Sci. USA 95, 3178–3181 (1998).
Bugga, L., Gadient, R. A., Kwan, K., Stewart, C. L. &
Patterson, P. H. Analysis of neuronal and glial
phenotypes in brains of mice deficient in leukemia
inhibitory factor. J. Neurobiol. 36, 509–524 (1998).
Ware, C. B. et al. Targeted disruption of the low-affinity
leukemia inhibitory factor receptor gene causes
placental, skeletal, neural and metabolic defects and
results in perinatal death. Development 121,
1283–1299 (1995).
Nakashima, K. et al. Developmental requirement of
gp130 signaling in neuronal survival and astrocyte
differentiation. J. Neurosci. 19, 5429–5434 (1999).
Sendtner, M. et al. Cryptic physiological trophic
support of motoneurons by LIF revealed by double
gene targeting of CNTF and LIF. Curr. Biol. 6,
686–694 (1996).
Holtmann, B. et al. Triple knock-out of CNTF, LIF,
and CT-1 defines cooperative and distinct roles of these
neurotrophic factors for motoneuron maintenance and
function. J. Neurosci. 25, 1778–1787 (2005).
Johe, K. K., Hazel, T. G., Muller, T.,
Dugich-Djordjevic, M. M. & McKay, R. D. Single factors
direct the differentiation of stem cells from the fetal
and adult central nervous system. Genes Dev. 10,
3129–3140 (1996).
Rajan, P. & McKay, R. D. Multiple routes to astrocytic
differentiation in the CNS. J. Neurosci. 18,
3620–3629 (1998).
Bonaguidi, M. A. et al. LIF and BMP signaling
generate separate and discrete types of GFAPexpressing cells. Development 132, 5503–5514
(2005).
REVIEWS
35. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M.
& Alvarez-Buylla, A. Subventricular zone astrocytes
are neural stem cells in the adult mammalian brain.
Cell 97, 703–16 (1999).
Shows that Gfap-expressing cells in the adult mouse
SVZ behave as NSCs both in vitro and in vivo.
36. Garcia, A. D., Doan, N. B., Imura, T., Bush, T. G. &
Sofroniew, M. V. GFAP-expressing progenitors are the
principal source of constitutive neurogenesis in adult
mouse forebrain. Nature Neurosci. 7, 1233–1241
(2004).
37. Emsley, J. G. & Hagg, T. Endogenous and exogenous
ciliary neurotrophic factor enhances forebrain
neurogenesis in adult mice. Exp. Neurol. 183,
298–310 (2003).
38. Kokoeva, M. V., Yin, H. & Flier, J. S. Neurogenesis in
the hypothalamus of adult mice: potential role in
energy balance. Science 310, 679–683 (2005).
Provides evidence that CNTF influences body
weight through effects on neurogenesis in the
hypothalamus, raising interesting questions about
the relationship between behaviour and
neurogenesis in novel brain areas.
39. Bauer, S. & Patterson, P. H. Leukemia inhibitory factor
promotes neural stem cell self-renewal in the adult
brain. J. Neurosci. 26, 12089–12099 (2006).
40. Vallieres, L., Campbell, I. L., Gage, F. H. &
Sawchenko, P. E. Reduced hippocampal neurogenesis
in adult transgenic mice with chronic astrocytic
production of interleukin-6. J. Neurosci. 22, 486–492
(2002).
41. Doetsch, F., Garcia-Verdugo, J. M. & Alvarez-Buylla, A.
Cellular composition and three-dimensional
organization of the subventricular germinal zone in the
adult mammalian brain. J. Neurosci. 17, 5046–5061
(1997).
42. Imura, T., Kornblum, H. I. & Sofroniew, M. V. The
predominant neural stem cell isolated from postnatal
and adult forebrain but not early embryonic forebrain
expresses GFAP. J. Neurosci. 23, 2824–2832 (2003).
43. Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. &
Alvarez-Buylla, A. Astrocytes give rise to new neurons
in the adult mammalian hippocampus. J. Neurosci.
21, 7153–7160 (2001).
44. Magavi, S. S., Leavitt, B. R. & Macklis, J. D. Induction
of neurogenesis in the neocortex of adult mice. Nature
405, 951–955 (2000).
The first paper to show that repair in the adult
brain could be induced from endogenous neural
progenitor cells.
45. Chen, J., Magavi, S. S. & Macklis, J. D. Neurogenesis
of corticospinal motor neurons extending spinal
projections in adult mice. Proc. Natl Acad. Sci. USA
101, 16357–16362 (2004).
46. Agasse, F., Roger, M. & Coronas, V. Neurogenic and
intact or apoptotic non-neurogenic areas of adult
brain release diffusible molecules that differentially
modulate the development of subventricular zone
cell cultures. Eur. J. Neurosci. 19, 1459–1468
(2004).
47. Banner, L. R., Moayeri, N. N. & Patterson, P. H.
Leukemia inhibitory factor is expressed in astrocytes
following cortical brain injury. Exp. Neurol. 147, 1–9
(1997).
48. Banner, L. R. & Patterson, P. H. Major changes in the
expression of the mRNAs for cholinergic
differentiation factor/leukemia inhibitory factor and its
receptor after injury to adult peripheral nerves and
ganglia. Proc. Natl Acad. Sci. USA 91, 7109–7113
(1994).
The first demonstration that LIF is an important
mediator of neural injury responses. This paper
identifies the timecourse and cellular source of Lif
expression after peripheral nerve injury in the
adult.
49. Bauer, S. et al. Leukemia inhibitory factor is a key
signal for injury-induced neurogenesis in the adult
mouse olfactory epithelium. J. Neurosci. 23,
1792–1803 (2003).
The first study to show that LIF is crucial for injuryinduced neuron regeneration in vivo.
50. Jankowsky, J. L. & Patterson, P. H. Differential
regulation of cytokine expression following
pilocarpine-induced seizure. Exp. Neurol. 159,
333–346 (1999).
51. Minami, M. et al. Kainic acid induces leukemia
inhibitory factor mRNA expression in the rat brain:
differences in the time course of mRNA expression
between the dentate gyrus and hippocampal CA1/CA3
subfields. Brain Res. Mol. Brain Res. 107, 39–46
(2002).
52. Sriram, K., Benkovic, S. A., Hebert, M. A., Miller, D. B.
& O’Callaghan, J. P. Induction of gp130-related
cytokines and activation of JAK2/STAT3 pathway in
astrocytes precedes up-regulation of glial fibrillary
acidic protein in the 1-methyl-4-phenyl-1, 2, 3,
6-tetrahydropyridine model of neurodegeneration: key
signaling pathway for astrogliosis in vivo? J. Biol.
Chem. 279, 19936–19947 (2004).
53. Suzuki, S. et al. Immunohistochemical detection of
leukemia inhibitory factor after focal cerebral ischemia in
rats. J. Cereb. Blood Flow Metab. 20, 661–668 (2000).
54. Getchell, T. V., Shah, D. S., Partin, J. V., Subhedar, N. K.
& Getchell, M. L. Leukemia inhibitory factor mRNA
expression is upregulated in macrophages and
olfactory receptor neurons after target ablation.
J. Neurosci. Res. 67, 246–254 (2002).
55. Nan, B., Getchell, M. L., Partin, J. V. & Getchell, T. V.
Leukemia inhibitory factor, interleukin-6, and their
receptors are expressed transiently in the olfactory
mucosa after target ablation. J. Comp. Neurol. 435,
60–77 (2001).
56. Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory
blockade restores adult hippocampal neurogenesis.
Science 302, 1760–1765 (2003).
57. Ekdahl, C. T., Claasen, J. H., Bonde, S., Kokaia, Z. &
Lindvall, O. Inflammation is detrimental for
neurogenesis in adult brain. Proc. Natl Acad. Sci. USA
100, 13632–13637 (2003).
58. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z. &
Lindvall, O. Neuronal replacement from endogenous
precursors in the adult brain after stroke. Nature Med.
8, 963–970 (2002).
59. Yamashita, T. et al. Subventricular zone-derived
neuroblasts migrate and differentiate into mature
neurons in the post-stroke adult striatum. J. Neurosci.
26, 6627–6636 (2006).
60. Zhang, R. et al. Activated neural stem cells contribute to
stroke-induced neurogenesis and neuroblast migration
toward the infarct boundary in adult rats. J. Cereb.
Blood Flow Metab. 24, 441–448 (2004).
61. Felling, R. J. et al. Neural stem/progenitor cells
participate in the regenerative response to perinatal
hypoxia/ischemia. J. Neurosci. 26, 4359–4369 (2006).
62. Hoehn, B. D., Palmer, T. D. & Steinberg, G. K.
Neurogenesis in rats after focal cerebral ischemia is
enhanced by indomethacin. Stroke 36, 2718–2724
(2005).
63. Kluska, M. M., Witte, O. W., Bolz, J. & Redecker, C.
Neurogenesis in the adult dentate gyrus after cortical
infarcts: effects of infarct location, N-methyl-Daspartate receptor blockade and anti-inflammatory
treatment. Neuroscience 135, 723–735 (2005).
64. Suzuki, S. et al. Activation of cytokine signaling
through leukemia inhibitory factor receptor (LIFR)/
gp130 attenuates ischemic brain injury in rats.
J. Cereb. Blood Flow Metab. 25, 685–693 (2005).
65. Rao, M. S. et al. Leukemia inhibitory factor mediates
an injury response but not a target-directed
developmental transmitter switch in sympathetic
neurons. Neuron 11, 1175–1185 (1993).
Highlights and clarifies the importance of LIF’s role in
mediating the phenotypic alteration in neuropeptide
synthesis by sensory neurons after injury.
66. Zigmond, R. E. & Sun, Y. Regulation of neuropeptide
expression in sympathetic neurons. Paracrine and
retrograde influences. Ann. NY Acad. Sci. 814,
181–197 (1997).
67. Holmberg, K. H. & Patterson, P. H. Leukemia inhibitory
factor is a key regulator of astrocytic, microglial and
neuronal responses in a low-dose pilocarpine injury
model. Brain Res. 1075, 26–35 (2006).
68. Stanke, M. et al. Target-dependent specification of the
neurotransmitter phenotype: cholinergic differentiation
of sympathetic neurons is mediated in vivo by gp 130
signaling. Development 133, 141–150 (2006).
69. Ito, Y. et al. Temporal expression of mRNAs for
neuropoietic cytokines, interleukin-11 (IL-11),
oncostatin M (OSM), cardiotrophin-1 (CT-1) and their
receptors (IL-11Rα and OSMRβ) in peripheral nerve
injury. Neurochem. Res. 25, 1113–1118 (2000).
70. Ito, Y. et al. Expression of mRNAs for ciliary
neurotrophic factor (CNTF), leukemia inhibitory factor
(LIF), interleukin-6 (IL-6), and their receptors (CNTFR
α, LIFR β, IL-6R α, and gp130) in human peripheral
neuropathies. Neurochem. Res. 26, 51–58 (2001).
71. Stockli, K. A. et al. Molecular cloning, expression and
regional distribution of rat ciliary neurotrophic factor.
Nature 342, 920–923 (1989).
72. Friedman, B. et al. Regulation of ciliary neurotrophic
factor expression in myelin-related Schwann cells
in vivo. Neuron 9, 295–305 (1992).
73. Curtis, R. et al. Retrograde axonal transport of ciliary
neurotrophic factor is increased by peripheral nerve
injury. Nature 365, 253–255 (1993).
74. Curtis, R. et al. Retrograde axonal transport of LIF is
increased by peripheral nerve injury: correlation with
increased LIF expression in distal nerve. Neuron 12,
191–204 (1994).
75. Thompson, S. W., Vernallis, A. B., Heath, J. K. &
Priestley, J. V. Leukaemia inhibitory factor is
retrogradely transported by a distinct population of
adult rat sensory neurons: co-localization with trkA
and other neurochemical markers. Eur. J. Neurosci. 9,
1244–1251 (1997).
76. Bennett, T. M. et al. Anterograde transport of
leukemia inhibitory factor within transected sciatic
nerves. Muscle Nerve 22, 78–87 (1999).
77. Sendtner, M., Kreutzberg, G. W. & Thoenen, H. Ciliary
neurotrophic factor prevents the degeneration of
motor neurons after axotomy. Nature 345, 440–441
(1990).
One of the earliest demonstrations that CNTF is an
important trophic factor for motor neurons after
injury.
78. Cheema, S. S., Richards, L., Murphy, M. & Bartlett, P. F.
Leukemia inhibitory factor prevents the death of
axotomised sensory neurons in the dorsal root ganglia
of the neonatal rat. J. Neurosci. Res. 37, 213–218
(1994).
79. Ikeda, K., Iwasaki, Y., Shiojima, T. & Kinoshita, M.
Neuroprotective effect of various cytokines on
developing spinal motoneurons following axotomy.
J. Neurol. Sci. 135, 109–113 (1996).
80. Murphy, P. G. et al. Reciprocal actions of interleukin-6
and brain-derived neurotrophic factor on rat and
mouse primary sensory neurons. Eur. J. Neurosci. 12,
1891–1899 (2000).
81. Murphy, M., Reid, K., Hilton, D. J. & Bartlett, P. F.
Generation of sensory neurons is stimulated by
leukemia inhibitory factor. Proc. Natl Acad. Sci. USA
88, 3498–3501 (1991).
82. Martinou, J. C., Martinou, I. & Kato, A. C. Cholinergic
differentiation factor (CDF/LIF) promotes survival of
isolated rat embryonic motoneurons in vitro. Neuron
8, 737–744 (1992).
83. Masu, Y. et al. Disruption of the CNTF gene results in
motor neuron degeneration. Nature 365, 27–32
(1993).
84. Hughes, R. A., Sendtner, M. & Thoenen, H. Members
of several gene families influence survival of rat
motoneurons in vitro and in vivo. J. Neurosci. Res. 36,
663–671 (1993).
85. Cheema, S. S., Richards, L. J., Murphy, M. &
Bartlett, P. F. Leukaemia inhibitory factor rescues
motoneurones from axotomy-induced cell death.
Neuroreport 5, 989–992 (1994).
86. Pavelko, K. D. et al. Interleukin-6 protects anterior
horn neurons from lethal virus-induced injury.
J. Neurosci. 23, 481–492 (2003).
87. Ikeda, K., Iwasaki, Y., Tagaya, N., Shiojima, T. &
Kinoshita, M. Neuroprotective effect of cholinergic
differentiation factor/leukemia inhibitory factor on
wobbler murine motor neuron disease. Muscle Nerve
18, 1344–1347 (1995).
88. Ikeda, K. et al. Coadministration of interleukin-6 (IL-6)
and soluble IL-6 receptor delays progression of
wobbler mouse motor neuron disease. Brain Res.
726, 91–97 (1996).
89. Kurek, J. B. et al. LIF (AM424), a promising growth
factor for the treatment of ALS. J. Neurol. Sci. 160,
S106–S113 (1998).
90. Azari, M. F., Galle, A., Lopes, E. C., Kurek, J. &
Cheema, S. S. Leukemia inhibitory factor by systemic
administration rescues spinal motor neurons in the
SOD1 G93A murine model of familial amyotrophic
lateral sclerosis. Brain Res. 922, 144–147 (2001).
91. Feeney, S. J. et al. The effect of leukaemia inhibitory
factor on SOD1 G93A murine amyotrophic lateral
sclerosis. Cytokine 23, 108–118 (2003).
92. Pun, S., Santos, A. F., Saxena, S., Xu, L. & Caroni, P.
Selective vulnerability and pruning of phasic
motoneuron axons in motoneuron disease alleviated
by CNTF. Nature Neurosci. 9, 408–419 (2006).
93. Hurko, O. & Walsh, F. S. Novel drug development for
amyotrophic lateral sclerosis. J. Neurol. Sci. 180,
21–28 (2000).
94. Davis, I. D. et al. A randomized, double-blinded,
placebo-controlled phase II trial of recombinant
human leukemia inhibitory factor (rhuLIF, emfilermin,
AM424) to prevent chemotherapy-induced peripheral
neuropathy. Clin. Cancer Res. 11, 1890–1898
(2005).
REVIEWS
95. Bloch, J. et al. Neuroprotective gene therapy for
Huntington’s disease, using polymer-encapsulated
cells engineered to secrete human ciliary neurotrophic
factor: results of a phase I study. Hum. Gene Ther. 15,
968–975 (2004).
96. Pennica, D. et al. Cardiotrophin-1, a cytokine present
in embryonic muscle, supports long-term survival of
spinal motoneurons. Neuron 17, 63–74 (1996).
97. Oppenheim, R. W. et al. Cardiotrophin-1, a musclederived cytokine, is required for the survival of
subpopulations of developing motoneurons.
J. Neurosci. 21, 1283–1291 (2001).
98. Lesbordes, J. C. et al. Therapeutic benefits of
cardiotrophin-1 gene transfer in a mouse model of
spinal muscular atrophy. Hum. Mol. Genet. 12,
1233–1239 (2003).
99. Tham, S. et al. Leukemia inhibitory factor enhances
the regeneration of transected rat sciatic nerve and
the function of reinnervated muscle. J. Neurosci. Res.
47, 208–215 (1997).
100. Cafferty, W. B. J. et al. Leukemia inhibitory factor
determines the growth status of injured adult sensory
neurons. J. Neurosci. 21, 7161–7170 (2001).
A key demonstration of the importance of LIF for
peripheral nerve regeneration. It describes for the
first time a role for LIF in mediating a switch in the
capacity for growth by sensory neurons following
‘conditioning lesions’.
101. Hirota, H., Kiyama, H., Kishimoto, T. & Taga, T.
Accelerated nerve regeneration in mice by
upregulated expression of interleukin (IL) 6 and IL-6
receptor after trauma. J. Exp. Med. 183, 2627–2634
(1996).
102. Zhong, J., Dietzel, I. D., Wahle, P., Kopf, M. &
Heumann, R. Sensory impairments and delayed
regeneration of sensory axons in interleukin-6deficient mice. J. Neurosci. 19, 4305–4313 (1999).
103. Cafferty, W. B. et al. Conditioning injury-induced spinal
axon regeneration fails in interleukin-6 knock-out
mice. J. Neurosci. 24, 4432–4443 (2004).
104. Cao, Z. et al. The cytokine interleukin-6 is sufficient
but not necessary to mimic the peripheral conditioning
lesion effect on axonal growth. J. Neurosci. 26,
5565–5573 (2006).
105. Blesch, A. et al. Leukemia inhibitory factor augments
neurotrophin expression and corticospinal axon
growth after adult CNS injury. J. Neurosci. 19,
3556–3566 (1999).
106. Fisher, J. et al. Increased post-traumatic survival of
neurons in IL-6-knockout mice on a background of EAE
susceptibility. J. Neuroimmunol. 119, 1–9 (2001).
107. Barres, B. A., Schmid, R., Sendnter, M. & Raff, M. C.
Multiple extracellular signals are required for longterm oligodendrocyte survival. Development 118,
283–295 (1993).
108. Barres, B. A. et al. Ciliary neurotrophic factor
enhances the rate of oligodendrocyte generation. Mol.
Cell. Neurosci. 8, 146–156 (1996).
109. Ishibashi, T. et al. Astrocytes promote myelination in
response to electrical impulses. Neuron 49, 823–832
(2006).
Describes a novel mechanism by which LIF is crucial
for the myelination of developing axons.
110. Schonrock, L. M., Gawlowski, G. & Bruck, W.
Interleukin-6 expression in human multiple sclerosis
lesions. Neurosci. Lett. 294, 45–48 (2000).
111. Vanderlocht, J. et al. Leukemia inhibitory factor is
produced by myelin-reactive T cells from multiple
sclerosis patients and protects against tumor necrosis
factor-α-induced oligodendrocyte apoptosis.
J. Neurosci. Res. 83, 763–774 (2006).
112. Butzkueven, H., Emery, B., Cipriani, T., Marriott, M. P.
& Kilpatrick, T. J. Endogenous leukemia inhibitory
factor production limits autoimmune demyelination
and oligodendrocyte loss. Glia 53, 696–703 (2006).
113. Linker, R. A. et al. CNTF is a major protective factor in
demyelinating CNS disease: a neurotrophic cytokine
as modulator in neuroinflammation. Nature Med. 8,
620–624 (2002).
114. Butzkueven, H. et al. LIF receptor signaling limits
immune-mediated demyelination by enhancing
oligodendrocyte survival. Nature Med. 8, 613–619
(2002).
Along with reference 113, this study highlights the
beneficial role that CNTF and LIF signalling have in
promoting oligodendrocyte survival in an animal
model of multiple sclerosis.
115. Laura, M., Gregson, N. A., Curmi, Y. & Hughes, R. A.
Efficacy of leukemia inhibitory factor in experimental
autoimmune neuritis. J. Neuroimmunol. 133, 56–59
(2002).
116. Emery, B. et al. Suppressor of cytokine signaling 3
limits protection of leukemia inhibitory factor receptor
signaling against central demyelination. Proc. Natl
Acad. Sci. USA 103, 7859–7864 (2006).
117. Hoffmann, V., Pohlau, D., Przuntek, H., Epplen, J. T. &
Hardt, C. A null mutation within the ciliary
neurotrophic factor (CNTF)-gene: implications for
susceptibility and disease severity in patients with
multiple sclerosis. Genes Immun. 3, 53–55 (2002).
118. Vanderlocht, J., Burzykowski, T., Somers, V., Stinissen, P.
& Hellings, N. No association of leukemia inhibitory
factor (LIF) DNA polymorphisms with multiple
sclerosis. J. Neuroimmunol. 171, 189–192 (2006).
119. Giess, R. et al. Association of a null mutation in the
CNTF gene with early onset of multiple sclerosis. Arch.
Neurol. 59, 407–409 (2002).
120. Zang da, W. & Cheema, S. S. Leukemia inhibitory
factor promotes recovery of locomotor function
following spinal cord injury in the mouse.
J. Neurotrauma 20, 1215–1222 (2003).
121. Kerr, B. J. & Patterson, P. H. Leukemia inhibitory
factor promotes oligodendrocyte survival after spinal
cord injury. Glia 51, 73–79 (2005).
Along with reference 120, this paper extends the
observation that LIF can promote oligodendrocyte
survival in models of spinal cord injury.
122. Kaplin, A. I. et al. IL-6 induces regionally selective
spinal cord injury in patients with the
neuroinflammatory disorder transverse myelitis.
J. Clin. Invest. 115, 2731–2741 (2005).
123. Klein, M. A. et al. Impaired neuroglial activation in
interleukin-6 deficient mice. Glia 19, 227–233 (1997).
124. Sugiura, S. et al. Leukaemia inhibitory factor is
required for normal inflammatory responses to injury
in the peripheral and central nervous systems in vivo
and is chemotactic for macrophages in vitro. Eur. J.
Neurosci. 12, 457–466 (2000).
125. Martin, A., Hofmann, H. D. & Kirsch, M. Glial reactivity
in ciliary neurotrophic factor-deficient mice after optic
nerve lesion. J. Neurosci. 23, 5416–5424 (2003).
126. Swartz, K. R. et al. Interleukin-6 promotes posttraumatic healing in the central nervous system. Brain
Res. 896, 86–95 (2001).
127. Kerr, B. J. & Patterson, P. H. Potent pro-inflammatory
actions of leukemia inhibitory factor in the spinal cord
of the adult mouse. Exp. Neurol. 188, 391–407 (2004).
128. Lacroix, S., Chang, L., Rose-John, S. & Tuszynski, M. H.
Delivery of hyper-interleukin-6 to the injured spinal
cord increases neutrophil and macrophage infiltration
and inhibits axonal growth. J. Comp. Neurol. 454,
213–228 (2002).
129. Banner, L. R., Patterson, P. H., Allchorne, A., Poole, S.
& Woolf, C. J. Leukemia inhibitory factor is an antiinflammatory and analgesic cytokine. J. Neurosci. 18,
5456–5462 (1998).
An important description of LIF’s anti-inflammatory
actions after cutaneous tissue injury, and the
implications of this function for regulating
inflammatory hyperalgesia.
130. Thompson, S. W., Dray, A. & Urban, L. Leukemia
inhibitory factor induces mechanical allodynia but not
thermal hyperalgesia in the juvenile rat. Neuroscience
71, 1091–1094 (1996).
131. Tofaris, G. K., Patterson, P. H., Jessen, K. R. &
Mirsky, R. Denervated Schwann cells attract
macrophages by secretion of leukemia inhibitory
factor (LIF) and monocyte chemoattractant protein-1
in a process regulated by interleukin-6 and LIF.
J. Neurosci. 22, 6696–6703 (2002).
132. Gadient, R. A. & Otten, U. Postnatal expression of
interleukin-6 (IL-6) and IL-6 receptor (IL-6R) mRNAs in
rat sympathetic and sensory ganglia. Brain Res. 724,
41–46 (1996).
133. Tamura, S., Morikawa, Y. & Senba, E. Localization of
oncostatin M receptor β in adult and developing CNS.
Neuroscience 119, 991–997 (2003).
134. Morikawa, Y. et al. Essential function of oncostatin M
in nociceptive neurons of dorsal root ganglia.
J. Neurosci. 24, 1941–1947 (2004).
135. DeLeo, J. A., Colburn, R. W., Nichols, M. & Malhotra,
A. Interleukin-6-mediated hyperalgesia/allodynia and
increased spinal IL-6 expression in a rat
mononeuropathy model. J. Interferon Cytokine Res.
16, 695–700 (1996).
136. Vissers, K. C., De Jongh, R. F., Hoffmann, V. L. &
Meert, T. F. Exogenous interleukin-6 increases cold
allodynia in rats with a mononeuropathy. Cytokine 30,
154–159 (2005).
137. Flatters, S. J., Fox, A. J. & Dickenson, A. H. Spinal
interleukin-6 (IL-6) inhibits nociceptive transmission
following neuropathy. Brain Res. 984, 54–62 (2003).
138. Xu, X. J. et al. Nociceptive responses in interleukin-6deficient mice to peripheral inflammation and
peripheral nerve section. Cytokine 9, 1028–1033
(1997).
139. Ramer, M. S., Murphy, P. G., Richardson, P. M. &
Bisby, M. A. Spinal nerve lesion-induced
mechanoallodynia and adrenergic sprouting in sensory
ganglia are attenuated in interleukin-6 knockout mice.
Pain 78, 115–121 (1998).
140. Murphy, P. G. et al. Endogenous interleukin-6
contributes to hypersensitivity to cutaneous stimuli
and changes in neuropeptides associated with chronic
nerve constriction in mice. Eur. J. Neurosci. 11,
2243–2253 (1999).
141. Brown, A. S. Prenatal infection as a risk factor for
schizophrenia. Schizophr. Bull. 32, 200–202 (2006).
142. Shi, L., Fatemi, S. H., Sidwell, R. W. & Patterson, P. H.
Maternal influenza infection causes marked behavioral
and pharmacological changes in the offspring.
J. Neurosci. 23, 297–302 (2003).
Using mice, this paper shows that a known risk
factor for schizophrenia, maternal respiratory
infection, strongly influences behaviour in the adult
offspring. It also introduces a novel model of
activation of the maternal immune system, using
the dsRNA poly(I:C).
143. Samuelsson, A. M., Jennische, E., Hansson, H. A. &
Holmang, A. Prenatal exposure to interleukin-6 results
in inflammatory neurodegeneration in hippocampus
with NMDA/GABAA dysregulation and impaired spatial
learning. Am. J. Physiol. Regul. Integr. Comp. Physiol.
290, R1345–R1356 (2006).
144. Juttler, E., Tarabin, V. & Schwaninger, M. Interleukin-6
(IL-6): a possible neuromodulator induced by neuronal
activity. Neuroscientist 8, 268–275 (2002).
145. Jankowsky, J. L., Derrick, B. E. & Patterson, P. H.
Cytokine responses to LTP induction in the rat
hippocampus: a comparison of in vitro and in vivo
techniques. Learn Mem. 7, 400–412 (2000).
146. Bellinger, F. P., Madamba, S. G., Campbell, I. L. &
Siggins, G. R. Reduced long-term potentiation in the
dentate gyrus of transgenic mice with cerebral
overexpression of interleukin-6. Neurosci. Lett. 198,
95–98 (1995).
147. Campbell, I. L. et al. Neurologic disease induced in
transgenic mice by cerebral overexpression of
interleukin 6. Proc. Natl Acad. Sci. USA 90,
10061–10065 (1993).
148. Li, A. J., Katafuchi, T., Oda, S., Hori, T. & Oomura, Y.
Interleukin-6 inhibits long-term potentiation in rat
hippocampal slices. Brain Res. 748, 30–38 (1997).
149. Tancredi, V. et al. The inhibitory effects of interleukin-6 on
synaptic plasticity in the rat hippocampus are associated
with an inhibition of mitogen-activated protein kinase
ERK. J. Neurochem. 75, 634–643 (2000).
150. Balschun, D. et al. Interleukin-6: a cytokine to forget.
FASEB J. 18, 1788–1790 (2004).
The authors use anti-IL-6 antibody injections to
show the importance of endogenous IL-6 in LTP and
long-term memory, and thereby strongly extend
work on the Il-6 knockout and experiments using
application of exogenous IL-6.
151. Braida, D. et al. Cognitive function in young and adult
IL (interleukin)-6 deficient mice. Behav. Brain Res.
153, 423–429 (2004).
152. Heyser, C. J., Masliah, E., Samimi, A., Campbell, I. L. &
Gold, L. H. Progressive decline in avoidance learning
paralleled by inflammatory neurodegeneration in
transgenic mice expressing interleukin 6 in the brain.
Proc. Natl Acad. Sci. USA 94, 1500–1555 (1997).
153. Ma, T. C. & Zhu, X. Z. Effects of intrahippocampal
infusion of interleukin-6 on passive avoidance and
nitrite and prostaglandin levels in the hippocampus in
rats. Arzneimittelforschung 50, 227–231 (2000).
154. Gruol, D. L. & Nelson, T. E. Purkinje neuron physiology
is altered by the inflammatory factor interleukin-6.
Cerebellum 4, 198–205 (2005).
155. Penkowa, M., Molinero, A., Carrasco, J. & Hidalgo, J.
Interleukin-6 deficiency reduces the brain
inflammatory response and increases oxidative
stress and neurodegeneration after kainic acidinduced seizures. Neuroscience 102, 805–818
(2001).
The Il-6 knockout is used here to demonstrate the
importance of endogenous IL-6 in regulating
seizure threshold, and presumably the balance of
excitation and inhibition in the CNS.
156. Samland, H. et al. Profound increase in sensitivity to
glutamatergic- but not cholinergic agonist-induced
seizures in transgenic mice with astrocyte production
of IL-6. J. Neurosci. Res. 73, 176–187 (2003).
REVIEWS
157. Kraves, S. & Weitz, C. J. A role for cardiotrophin-like
cytokine in the circadian control of mammalian
locomotor activity. Nature Neurosci. 9, 212–219
(2006).
158. Swiergiel, A. H. & Dunn, A. J. Feeding, exploratory,
anxiety- and depression-related behaviors are not
altered in interleukin-6-deficient male mice. Behav.
Brain Res. 171, 94–108 (2006).
159. Dantzer, R. Cytokine-induced sickness behaviour: a
neuroimmune response to activation of innate
immunity. Eur. J. Pharmacol. 500, 399–411 (2004).
160. Morrow, J. D. & Opp, M. R. Sleep–wake behavior
and responses of interleukin-6-deficient mice to sleep
deprivation. Brain Behav. Immun. 19, 28–39 (2005).
161. Alleva, E. et al. Behavioural characterization of
interleukin-6 overexpressing or deficient mice during
agonistic encounters. Eur. J. Neurosci. 10,
3664–3672 (1998).
162. Chesnokova, V. & Melmed, S. Minireview: Neuroimmuno-endocrine modulation of the hypothalamicpituitary-adrenal (HPA) axis by gp130 signaling
molecules. Endocrinology 143, 1571–1574 (2002).
163. Butterweck, V., Prinz, S. & Schwaninger, M. The role of
interleukin-6 in stress-induced hyperthermia and
emotional behaviour in mice. Behav. Brain Res. 144,
49–56 (2003).
164. Swiergiel, A. H. & Dunn, A. J. Feeding, exploratory,
anxiety- and depression-related behaviors are not
altered in interleukin-6-deficient male mice. Behav.
Brain Res. 171, 94–108 (2006).
165. Kahl, K. G. et al. Cortisol, the cortisoldehydroepiandrosterone ratio, and pro-inflammatory
cytokines in patients with current major depressive
disorder comorbid with borderline personality
disorder. Biol. Psychiatry 59, 667–671 (2006).
166. Nunes, S. O. et al. An autoimmune or an inflammatory
process in patients with schizophrenia, schizoaffective
disorder, and in their biological relatives. Schizophr.
Res. 84, 180–182 (2006).
167. Pae, C. U. et al. Antipsychotic treatment may alter
T-helper (TH) 2 arm cytokines. Int. Immunopharmacol.
6, 666–671 (2006).
168. Pike, J. L. & Irwin, M. R. Dissociation of inflammatory
markers and natural killer cell activity in major
depressive disorder. Brain Behav. Immun. 20,
169–174 (2006).
169. Tsao, C. W., Lin, Y. S., Chen, C. C., Bai, C. H. & Wu, S. R.
Cytokines and serotonin transporter in patients with
major depression. Prog. Neuropsychopharmacol. Biol.
Psychiatry 30, 899–905 (2006).
170. Wichers, M. C. et al. Baseline immune activation as a
risk factor for the onset of depression during
interferon-α treatment. Biol. Psychiatry 60, 77–79
(2006).
171. Pechnick, R. N. et al. Reduced immobility in the forced
swim test in mice with a targeted deletion of the
leukemia inhibitory factor (LIF) gene.
Neuropsychopharmacology 29, 770–776 (2004).
172. Chourbaji, S. et al. IL-6 knockout mice exhibit
resistance to stress-induced development of depressionlike behaviors. Neurobiol. Dis. 23, 587–594 (2006).
173. Plata-Salaman, C. R. Cytokines and feeding
suppression: an integrative view from neurologic to
molecular levels. Nutrition 11, 674–677 (1995).
174. Fernandez-Moreno, C., Pichel, J. G., Chesnokova, V. &
De Pablo, F. Increased leptin and white adipose tissue
hypoplasia are sexually dimorphic in Lif null/Igf-I
haploinsufficient mice. FEBS Lett. 557, 64–68 (2004).
175. Rondinone, C. M. Adipocyte-derived hormones,
cytokines, and mediators. Endocrine 29, 81–90 (2006).
176. Prima, V. et al. Differential modulation of energy
balance by leptin, ciliary neurotrophic factor, and
leukemia inhibitory factor gene delivery: microarray
deoxyribonucleic acid-chip analysis of gene
expression. Endocrinology 145, 2035–2045 (2004).
177. Heinrich, P. C. et al. Principles of interleukin (IL)-6-type
cytokine signalling and its regulation. Biochem. J.
374, 1–20 (2003).
Acknowledgements
We thank K. Hamilton for help in preparing the manuscript,
and D. McDowell and B. Lease for administrative support on
the work done in the Patterson laboratory. Our research discussed here was supported by grants from the National
Institute of Neurological Disease and Stroke, the John
Douglas French Alzheimer’s Foundation, the McGrath
Foundation, a Cline Neuroscience Discovery Grant, and the
Roman Reed Spinal Cord Injury Research Fund of California.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
CLC | CNTF | CT-1 | GFAP | gp130 | IL-6 | JAK | LIF | neuropoietin
| STAT
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
amyotrophic lateral sclerosis | Huntington’s disease | multiple
sclerosis | schizophrenia
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The neuropoietic cytokine family in development, plasticity, disease

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