Role of cytokine signaling during nervous system development

Alyaa Mousa, Moiz Bakhiet, Alyaa Mousa, Moiz Bakhiet

Abstract

Cytokines are signaling proteins that were first characterized as components of the immune response, but have been found to have pleiotropic effects in diverse aspects of body function in health and disease. They are secreted by numerous cells and are used extensively in intercellular communications to produce different activities, including intricate processes engaged in the ontogenetic development of the brain. This review discusses factors involved in brain growth regulation and recent findings exploring cytokine signaling pathways during development of the central nervous system. In view of existing data suggesting roles for neurotropic cytokines in promoting brain growth and repair, these molecules and their signaling pathways might become targets for therapeutic intervention in neurodegenerative processes due to diseases, toxicity, or trauma.

Figures

Figure 1
Figure 1
A diagram showing the relationships between the major central nervous system (CNS); cell types Self- renewal.
Figure 2
Figure 2
IL-6 family cytokines and their receptors Receptor complexes are composed of the signaling subunits gp 130 (green), LIF- R (pink) and OSM-R (lilac) and specific ligand binding receptors. (For IL-6, IL-11R, CNTF-R, CT-1R and CIC/NNT-1/BSF-3-R). IL-6 and IL-11 signal via a homodimer of gp 130 whereas ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), and novel neurotrophin 1 (NNT-1) use a heterodimers of gp 130 and LIF-R. Leukemia inhibitory factor (LIF) and oncostatin M (OSM) do not use specific binding receptors. Binding of IL-6 cytokines will activate Janus Kinase-Signal Transducer, Activator of Transcription (JAK-STAT) and Mitogen-Activated Protein Kinase (MAPK) pathways.

References

    1. Ousman S.S., Kubes P. Immune surveillance in the central nervous system. Nat. Neurosci. 2012;15:1096–1101.
    1. Bakhiet M., Tjernlund A., Mousa A., Gad A., Strömblad S., Kuziel W.A., Seiger A., Andersson J. RANTES promotes growth and survival of human first-trimester forebrain astrocytes. Nat. Cell Biol. 2001;3:150–157.
    1. Thomson J.A., Itskovitz-Eldor J., Shapiro S.S., Waknitz M.A., Swiergiel J.J., Marshall V.S., Jones J.M. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–1147.
    1. Herschkowitz N., Kagan J., Zilles K. Neurobiological bases of behavioral development in the first year. Neuropediatrics. 1997;28:296–306.
    1. Corbin J.G., Nery S., Fishell G. Telencephalic cells take a tangent: Non-radial migration in the mammalian forebrain. Nat. Neurosci. 2001;4:1177–1182.
    1. Marin O., Rubenstein J.L. A long, remarkable journey: Tangential migration in the telencephalon. Nat. Rev. Neurosci. 2001;2:780–790.
    1. Temple S. The development of neural stem cells. Nature. 2001;414:112–117.
    1. Alvarez-Buylla A., Temple S. Stem cells in the developing and adult nervous system. J. Neurobiol. 1998;36:105–109.
    1. Gage F.H. Mammalian neural stem cells. Science. 2000;287:1433–1438.
    1. Van der Kooy D., Weiss S. Why stem cells? Science. 2000;287:1439–1441.
    1. Davis A.A., Temple S.A. Self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature. 1994;372:263–266.
    1. 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. 1996;10:3129–3140.
    1. Weiss S., Reynolds B.A., Vescovi A.L., Morshead C., Craig C.G., van der Kooy D. Is there a neural stem cell in the mammalian forebrain? Trends Neurosci. 1996;19:387–393.
    1. Qian X., Goderie S.K., Shen Q., Stern J.H., Temple S. Intrinsic programs of patterned cell lineages in isolated vertebrate CNS ventricular zone cells. Development. 1998;125:3143–3152.
    1. Gage F.H., Ray J., Fisher L.J. Isolation, Characterization, and use of Stem Cells from the CNS. Annu. Rev. Neurosci. 1995;18:159–192.
    1. Temple S., Alvarez-Buylla A. Stem cells in the adult mammalian central nervous system. Curr. Opin. Neurobiol. 1999;9:135–141.
    1. Luskin M.B., Pearlman A.L., Sanes J.R. Cell lineage in the cerebral cortex of the mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron. 1988;1:635–647.
    1. Price J., Thurlow L. Cell lineage in the rat cerebral cortex: A study using retroviral-mediated gene transfer. Development. 1988;104:473–82.
    1. Mayer-Proschel M., Kalyani A.J., Mujtaba T., Rao M.S. Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron. 1997;19:773–785.
    1. Rao M.S., Noble M., Mayer-Proschel M. A tripotential glial precursor cell is present in the developing spinal cord. Proc. Natl. Acad. Sci. USA. 1998;95:3996–4001.
    1. Shi J., Marinovich A., Barres B.A. Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J. Neurosci. 1998;18:4627–4636.
    1. Jacobson M. Developmental Neurobiology. Plenum Press; New York, NY, USA: 1991.
    1. Mousa A., Mustafa M., Kjaeldgaard A., Wahlberg L., Seiger A., Bakhiet M. Interactions between human embryonic forebrain cells and the cytokines interferon-gamma and interleukin-4. Int. J. Mol. Med. 1998;1:171–176.
    1. Mousa A., Seiger A., Kjaeldgaard A., Bakhiet M. Human first trimester forebrain cells express genes for inflammatory and anti-inflammatory cytokines. Cytokine. 1999;11:55–60.
    1. Xiao B.G., Mousa A., Kivisäkk P., Seiger A., Bakhiet M., Link H. Induction of beta-family chemokines mRNA in human embryonic astrocytes by inflammatory cytokines and measles virus protein. J. Neurocytol. 1998;27:575–580.
    1. Gregg C., Weiss S. CNTF/lif/gp130 receptor complex signaling maintains a VZ precursor differentiation gradient in the developing ventral forebrain. Development. 2005;132:565–578.
    1. Doetsch F., Alvarez-Buylla A. Network of tangential pathways for neuronal migration in adult mammalian brain. Proc. Natl. Acad. Sci. USA. 1996;93:14895–14900.
    1. Lois C., Garcia-Verdugo J.M., Alvarez-Buylla A. Chain migration of neuronal precursors. Science. 1996;271:978–981.
    1. Luskin M.B. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron. 1993;11:173–189.
    1. Lois C., Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994;264:1145–1148.
    1. Doetsch F., Garcia-Verdugo J.M., Alvarez-Buylla A. Cellular composition and three-dimensional organization of the sub-ventricular germinal zone in the adult mammalian brain. J. Neurosci. 1997;17:5046–5061.
    1. Morshead C.M., Reynolds B.A., Craig C.G., McBurney M.W., Staines W.A., Morassutti D., Weiss S., van der Kooy D. Neural stem cells in the adult mammalian forebraina relatively quiescent subpopulation of subependymal cells. Neuron. 1994;13:1071–1082.
    1. Gritti A., Frolichsthal-Schoeller P., Galli R., Parati E.A., Cova L., Pagano S.F., Bjornson C.R., Vescovi A.L. Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J. Neurosci. 1999;19:3287–3297.
    1. Reynolds B., Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255:1707–1710.
    1. Gritti A., Cova L., Parati E.A., Galli R., Vescovi A.L. Basic fibroblast growth factor supports the proliferation of epidermal growth factor-generated neuronal precursor cells of the adult mouse CNS. Neurosci. Lett. 1995;185:151–154.
    1. Fox I.J., Paucar A.A., Nakano I., Mottahedeh J., Dougherty J.D., Kornblum H.I. Developmental expression of glial fibrillary acidic protein mRNA in mouse forebrain germinal zones-implications for stem cell biology. Brain Res. Dev. Brain Res. 2004;153:121–125.
    1. Qian X., Shen Q., Goderie S.K., He W., Capela A., Davis A.A., Temple S. Timing of CNS cell generation: A programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron. 2000;28:69–80.
    1. Groszer M., Erickson R., Scripture-Adams D.D., Dougherty J.D., Le Belle J., Zack J.A., Geschwind D.H., Liu X., Kornblum H.I., Wu H. PTEN negatively regulates neural stem cell self-renewal by modulating G0–G1 cell cycle entry. Proc. Natl. Acad. Sci. USA. 2006;103:111–116.
    1. Groszer M., Erickson R., Scripture-Adams D.D., Lesche R., Trumpp A., Zack J.A., Kornblum H.I., Liu X., Wu H. Negative regulation of neural stem/progenitor cell proliferation by the PTEN tumor suppressor gene in vivo. Science. 2001;294:2186–2189.
    1. Nadarajah B., Brunstrom J.E., Grutzendler J., Wong R.O., Pearlman A.L. Two modes of radial migration in early development of the cerebral cortex. Nat. Neurosci. 2001;4:143–50.
    1. Rakic P. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 1972;145:61–83.
    1. O’Rourke N.A., Dailey M.E., Smith S.J., McConnell S.K. Diverse migratory pathways in the developing cerebral cortex. Science. 1992;258:299–302.
    1. Book K.J., Morest D.K. Migration of neuroblasts by perikaryal translocation: Role of cellular elongation and axonal outgrowth in the acoustic nuclei of the chick embryo medulla. J. Comp. Neurol. 1990;297:55–76.
    1. Morris N.R., Efimov V.P., Xiang X. Nuclear migration, nucleokinesis and lissencephaly. Trends Cell Biol. 1998;8:467–470.
    1. Bellion A., Baudoin J.P., Alvarez C., Bornens M., Metin C. Nucleokinesis in tangentially migrating neurons comprises two alternating phases: Forward migration of the Golgi/centrosome associated with centrosome splitting and myosin contraction at the rear. J. Neurosci. 2005;25:5691–5699.
    1. Schaar B.T., McConnell S.K. Cytoskeletal coordination during neuronal migration. Proc. Natl. Acad. Sci. USA. 2005;102:13652–13657.
    1. Higginbotham H.R., Gleeson J.G. The centrosome in neuronal development. Trends Neurosci. 2007;30:276–283.
    1. Vallee R.B., Seale G.E., Tsai J.W. Emerging roles for myosin II and cytoplasmic dynein in migrating neurons and growth cones. Trends Cell Biol. 2009;19:347–355.
    1. Gilman A., Goodman L.S., Hardman J.G., Limbird L.E. Pharmacological basis of therapeutics. McGraw-Hill Professional; New York, NY, USA: 2001.
    1. Besedovsky H.O., del Rey A., Klusman I., Furukawa H., Monge Arditi G., Kabiersch A. Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. J. Steroid Biochem. Mol. Biol. 1991;40:613–618.
    1. Breder C.D., Dinarello C.A., Saper C.B. Interleukin-1 immunoreactive innervation of the human hypothalamus. Science. 1988;240:321–324.
    1. Plata-Salaman C.R., Oomura Y., Kai Y. Tumor necrosis factor and interleukin-1 betaSuppression of food intake by direct action in the central nervous system. Brain Res. 1988;448:106–114.
    1. Sternberg E.M. Neural-immune interactions in health and disease. J. Clin. Invest. 1997;100:2641–2647.
    1. Simon R., Their M., Kruttgen A., Rose-John S., Weiergraber O., Heinrich P.C., Schroder J.M., Weis J. Human CNTF and related cytokines: Effects on DRG neurone survival. Neuroreport. 1995;7:153–157.
    1. Heinrich P.C., Behrmann I., Haan S., Hermanns H.M., Muller-Newen G., Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 2003;374:1–20.
    1. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994;76:253–262.
    1. Taga T., Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 1997;15:797–819.
    1. Fasnacht N., Muller W. Conditional gp130 deficient mouse mutants. Semin. Cell Dev. Biol. 2008;19:379–384.
    1. 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. 2001;21:7642–7653.
    1. Silver J.S., Hunter C.A. gp130 at the nexus of inflammation, autoimmunity, and cancer. J. Leukoc. Biol. 2010;88:1145–1156.
    1. Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B., Taniguchi T., Hirano T., Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988;241:825–828.
    1. Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990;63:1149–1157.
    1. Heinrich P.C., Behrmann I., Müller-Newen G., Schaper F., Graeve L. IL-6-type cytokine signalling through the gp130/JAK/STAT pathway. Biochem. J. 1998;334:297–314.
    1. Senaldi G., Varnum B.C., Sarmiento U., Starnes C., Lile J., Scully S., Guo J., Elliott G., McNinch J., Shaklee C.L., et al. Novel neurotrophin-1/B cell-stimulating factor-3: A cytokine of the IL-6 family. Proc. Natl. Acad. Sci. USA. 1999;96:11458–11463.
    1. Davis S., Aldrich T.H., Valenzuela D.M., Wong V.V., Furth M.E., Squinto S.P., Yancopoulos G.D. The receptor forciliary neurotrophic factor. Science. 1991;253:59–63.
    1. Davis S., Yancopoulos G.D. The molecular biology of the CNTF receptor. Curr. Opin. Nelurobiol. 1993;3:20–24.
    1. Novick D., Engelmann H., Wallach D., Rubinstein M. Soluble cytokine receptors are present in normal human urine. J. Exp. Med. 1989;170:1409–1414.
    1. Honda M., Yamamoto S., Cheng M., Yasukawa K., Suzuki H., Saito T., Osugi Y., Tokunaga T., Kishimoto T. Human soluble IL-6 receptor: Its detection and enhanced release by HIV infection. J. Immunol. 1992;148:2175–2180.
    1. Mackiewicz A., Schooltink H., Heinrich P.C., Rose-John S. Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. J. Immunol. 1992;149:2021–2027.
    1. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989;58:573–581.
    1. Jones S.A., Richards P.J., Scheller J., Rose-John S. IL-6 transsignaling: The in vivo consequences. J. Interf. Cytokine Res. 2005;25:241–253.
    1. Rose-John S. GP130 stimulation and the maintenance of stem cells. Trends Biotechnol. 2002;20:417–419.
    1. Humphrey R.K., Beattie G.M., Lopez A.D., Bucay N., King C.C., Firpo M., Rose-John S., Hayek A. Maintenance of pluripotency in human embryonic stem cells is Stat3 independent. Stem. Cells. 2004;22:522–530.
    1. Peters M., Schirmacher P., Goldschmitt J., Odenthal M., Peschel C., Dienes H.P., Fattori E., Ciliberto G., Meyer zum Büschenfelde K.H., Rose-John S. Extramedullary expansion of hematopoietic progenitor cells in IL-6/sIL-6R double transgenic mice. J. Exp. Med. 1997;185:755–766.
    1. Peters M., Müller A., Rose-John S. Interleukin-6 and soluble interleukin-6 receptor: Direct stimulation of gp130 and hematopoiesis. Blood. 1998;92:3495–3504.
    1. Audet J., Miller C.L., Rose-John S., Piret J.M., Eaves C.J. Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic cells. Proc. Natl. Acad. Sci. USA. 2001;98:1757–1762.
    1. Hacker C., Kirsch R.D., Ju X.-S., Hieronymus T., Gust T.C., Kuhl C., Jorgas T., Kurz S.M., Rose-John S., Yokota Y., et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat. Immunol. 2003;4:380–386.
    1. Campard D., Vasse M., Rose-John S., Poyer F., Lamacz M., Vannier J.P. Multilevel regulation of IL-6R by IL-6/sIL-6R fusion protein according to the primitiveness of the peripheral blood-derived CD133+ cells. Stem Cells. 2005;5:1302–1314.
    1. Atreya R., Mudter J., Finotto S., Müllberg J., Jostock T., Wirtz S., Schütz M., Bartsch B., Holtmann M., Becker C., et al. Blockade of IL-6 transsignaling abrogates established experimental colitis in mice by suppression of the antiapoptotic resistance of lamina propria T cells. Nat. Med. 2000;6:583–588.
    1. Becker C., Fantini M.C., Schramm C., Lehr H.A., Wirtz S., Nikolaev A., Burg J., Strand S., Kiesslich R., Huber S., et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity. 2004;21:491–501.
    1. Becker C., Fantini M.C., Wirtz S., Nikolaev A., Lehr H.A., Galle P.R., Rose-John S., Neurath M.F. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle. 2005;4:217–220.
    1. März P., Cheng J.-C., Gadient R.A., Patterson P., Stoyan T., Otten U., Rose-John S. Sympathetic neurons can produce and respond to interleukin-6. Proc. Natl. Acad. Sci. USA. 1998;95:3251–3256.
    1. März P., Otten U., Rose-John S. Neuronal activities of IL-6 type cytokines often depend on soluble cytokine receptors. Eur. J. Neurosci. 1999;11:2995–3004.
    1. Klouche M., Bhakdi S., Hemmes M., Rose-John S. Novel path of activation of primary human smooth muscle cells: Upregulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor. J. Immunol. 1999;163:4583–4589.
    1. Hurst S.M., Wilkinson T.S., McLoughlin R.M., Jones S., Horiuchi S., Yamamoto N., Rose-John S., Fuller G.M., Topley N., Jones S.A. Control of leukocyte infiltration during inflammation: IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment. Immunity. 2001;14:705–714.
    1. Mcloughlin R.M., Witowski J., Robson R.L., Wilkinson T.S., Hurst S.M., Williams A.S., Williams J.D., Rose-John S., Jones S.A., Topley N. Interplay between IFN-γ and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. J. Clin. Invest. 2003;112:598–607.
    1. Romano M., Sironi M., Toniatti C., Polentarutti N., Fruscella P., Ghezzi P., Faggioni R., Luini W., van Hinsbergh V., Sozzani S., et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997;6:315–325.
    1. Mendoçna Torres P.M., de Araujo E.G. Interleukin-6 increases the survival of retinal ganglion cells in vitro. J. Neuroimmunol. 2001;117:43–50.
    1. Hirota H., Kiyama H., Kishimoto T., Taga T. Accelerated nerve regeneration in mice by upregulated expression of interleukin-6 (IL-6) and IL-6 receptor after trauma. J. Exp. Med. 1996;183:2627–2634.
    1. Haggiag S., Chebath J., Revel M. Induction of myelin gene expression in Schwann cell cultures by an interleukin-6 receptor-interleukin-6 chimera. FEBS Lett. 1999;2:1–5.
    1. Brunello A.G., Weissenberger J., Kappeler A., Vallan C., Peters M., Rose-John S., Weis J. Astrocytic alterations in interleukin-6/soluble interleukin-6 receptor α double transgenic mice. Am. J. Pathol. 2000;157:1485–1493.
    1. Yang X.J., Chung D., Cepko C.L. Molecular cloning of the murine JAK1 protein tyrosine kinase and its expression in the mouse central nervous system. J. Neurosci. 1993;13:3006–3017.
    1. De-Fraja C., Conti L., Magrassi L., Govoni S., Cattaneo E. Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain. J. Neurosci. Res. 1998;54:320–330.
    1. Darnell J.E., Kerr I.M., Stark G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular proteins. Science. 1994;264:1415–1421.
    1. Akira S., Nishio Y., Inoue M., Wang X., We S., Matsusaka T., Yoshida K., Sudo T., Naruto M., Kishimot T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994;77:63–71.
    1. Lütticken C., Wegenka U.M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpu A.G., Wilks A.F., Yasukawa K., Taga T., et al. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994;263:89–92.
    1. Zhong Z., Wen Z., Darnell J.E. Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264:95–98.
    1. Raz R., Durbin J.E., Levy D.E. Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. J. Biol. Chem. 1994;269:24391–24395.
    1. Hirano T., Ishihara K., Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 2000;19:2548–2556.
    1. März P., Herget T., Lang E., Otten U., Rose-John S. Activation of gp130 by IL-6/soluble IL-6 receptor induces neuronal differentiation. Eur. J. Neurosci. 1998;9:2765–2773.
    1. Boeuf H., Hauss C., Graeve F.D., Baran N., Kedinger C. Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. J. Cell Biol. 1997;138:1207–1217.
    1. Niwa H., Burdon T., Chambers I., Smith A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 1998;12:2048–2060.
    1. Raz R., Lee C.K., Cannizzaro L.A., d’Eustachio P., Levy D.E. Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl. Acad. Sci. USA. 1999;96:2846–2851.
    1. Matsuda T., Nakamura T., Nakao K., Arai T., Katsuki M., Heike T., Yokota T. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO. J. 1999;18:4261–4269.
    1. Bonni A., Sun Y., Nadal-Vicens M., Bhatt A., Frank D.A., Rozovsky I., Stahl N., Yancopoulos G.D., Greenberg M.E. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science. 1997;278:477–483.
    1. Gu F., Hata R., Ma Y.J., Tanaka J., Mitsuda N., Kumon Y., Hanakawa Y., Hashimoto K., Nakajima K., Sakanaka M. Suppression of Stat3 promotes neurogenesis in cultured neural stem cells. J. Neurosci. Res. 2005;81:163–171.
    1. Yanagisawa M., Nakashima K., Taga T. STAT3-mediated astrocyte differentiation from mouse fetal neuroepithelial cells by mouse oncostatin M. Neurosci. Lett. 1999;269:169–172.
    1. Fukuda S., Abematsu M., Mori H., Yanagisawa M., Kagawa T., Nakashima K., Yoshimura A., Taga T. Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells. Mol. Cell Biol. 2007;27:4931–4937.
    1. Taylor M.K., Yeager K., Morrison S.J. Physiological Notch signaling promotes gliogenesis in the developing peripheral and central nervous systems. Development. 2007;134:2435–2447.
    1. Takeda K., Noguchi K., Shi W., Tanaka T., Matsumoto M., Yoshida N., Kishimoto T., Akira S. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA. 1997;94:3801–3804.
    1. Yoshida K., Taga T., Saito M., Suematsu S., Kumanogoh A., Tanaka T., Fujiwara H., Hirata M., Yamagami T., Nakahata T., et al. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc. Natl. Acad. Sci. USA. 1996;93:407–411.
    1. Guschin D., Rogers N., Briscoe J., Witthuhn B., Watling D., Horn F., Pellegrini S., Yasukawa K., Heinrich P., Stark G.R. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO. J. 1995;14:1421–1429.
    1. Ernst M., Oates A., Dunn A.R. Gp130-mediated signal transduction in embryonic stem cells involves activation of Jak and Ras/mitogen-activated protein kinase pathways. J. Biol. Chem. 1996;271:30136–30143.
    1. Rodig S.J., Meraz M.A., White J.M., Lampe P.A., Riley J.K., Arthur C.D., King K.L., Sheehan K.C., Yin L., Pennica D., et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93:373–383.
    1. Moon C., Yoo J.Y., Matarazzo V., Sung Y.K., Kim E.J., Ronnett G.V. Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation. Proc. Natl. Acad. Sci. USA. 2002;99:9015–9020.
    1. Pan J., Fukuda K., Kodama H., Sano M., Takahashi T., Makino S., Kato T., Manabe T., Hori S., Ogawa S. Involvement of gp130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart. Heart Vessel. 1998;4:199–208.
    1. Wu Y.Y., Bradshaw R.A. Induction of neurite outgrowth by interleukin-6 is accompanied by activation of Stat3 signaling pathway in a variant PC12 cell (E2) line. J. Biol. Chem. 1996;271:13023–13032.
    1. Wu Y.Y., Bradshaw R.A. Synergistic induction of neurite outgrowth by nerve growth factor or epidermal growth factor and interleukin-6 in PC12 cells. J. Biol. Chem. 1996;271:13033–13039.
    1. Ihara S., Nakajima K., Fukada T., Hibi M., Nagata S., Hirano T., Fukui Y. Dual control of neurite outgrowth by STAT3 and MAP kinase in PC12 cells stimulated with interleukin-6. EMBO J. 1997;16:5345–5352.
    1. Rajan P., McKay R.D.G. Multiple routes to astrocytic differentiation in the CNS. J. Neurosci. 1998;18:3620–3629.
    1. Rajan P., Symes A.J., Fink J.S. Stat proteins are activated by ciliary neurotrophic factor in cells of central nervous system origin. J. Neurosci. Res. 1996;43:403–411.
    1. Symes A., Lewis S., Corpus L., Rajan P., Hyman S.E., Fink J.S. STAT proteins participate in the regulation of the vasoactive intestinal peptide gene by the ciliary neurotrophic factor family of cytokines. Mol. Endocrinol. 1994;8:1750–1763.
    1. Hamanaka I., Saito Y., Yasukawa H., Kishimoto I., Kuwahara K., Miyamoto Y., Harada M., Ogawa E., Kajiyama N., Takahashi N., Izumi T., et al. Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo. Circ. Res. 2001;88:727–732.
    1. Stephanou A., Brar B.K., Knight R.A., Latchman D.S. Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters. Cell Death Differ. 2000;7:329–330.
    1. Sheng Z., Knowlton K., Chen J., Hoshijima M., Brown J.H., Chien K.R. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J. Biol. Chem. 1997;272:5783–5791.
    1. Shi Y., Wang W., Yourey P.A., Gohari S., Zukauskas D., Zhang J., Ruben S., Alderson R.F. Computational EST database analysis identifies a novel member of the neuropoietic cytokine family. Biochem. Biophys. Res. Commun. 1999;1:132–138.
    1. Auernhammer C.J., Isele N.B., Kopp F.B., Spoettl G., Cengic N., Weber M.M., Senaldi G., Engelhardt D. Novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) stimulates corticotroph function via a signal transducer and activator of transcription-dependent mechanism negatively regulated by suppressor of cytokine signaling-3. Endocrinology. 2003;4:1202–1210.
    1. Boulton T.G., Stahl N., Yancopoulos G.D. Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J. Biol. Chem. 1994;15:11648–11655.
    1. Guzzo C., Fazila N., Mat C., Gee K. Interleukin-27 Induces a STAT1/3- and NF-κB-dependent proinflammatory cytokine profile in human monocytes. J. Biol. Chem. 2012;287:8661.
    1. Dambacher J., Beigel F., Seiderer J., Haller D., Göke B., Auernhammer C.J., Brand S. Interleukin 31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is upregulated in inflammatory bowel disease. Gut. 2007;56:1257–1265.
    1. Zigmond R.E. gp130 cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury. Front. Mol. Neurosci. 2011;4:62.
    1. Sun F., He Z. Neuronal intrinsic barriers for axon regeneration in the adult CNS. Curr. Opin. Neurobiol. 2010;20:510–518.
    1. Pflanz S., Hibbert L., Mattson J., Rosales R., Vaisberg E., Bazan J.F., Phillips J.H., McClanahan T.K., de Waal Malefyt R., Kastelein R.A. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 2004;172:2225–2231.
    1. Levy D.E., Danell J.E., Jr. Stats: Transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 2002;3:651–662.
    1. Brivanlou A.H., Darnell J.E., Jr Signal transduction and the control of gene expression. Science. 2002;295:813–818.
    1. O’Shea J.J., Gadina M., Schreiber R.D. Cytokine signaling in 2002: New surprises in the Jak/Stat pathway. Cell. 2002;109:S121–S131.
    1. Guo Z., Jiang H., Xu X., Duan W., Mattson M.P. Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J. Biol. Chem. 2008;283:1754–1763.
    1. Repovic P., Benveniste E.N. Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia. J. Neurosci. 2002;22:5334–5343.
    1. Van Wagoner N.J., Benveniste E.N. Interleukin-6 expression and regulation in astrocytes. J. Neuroimmunol. 1999;100:124–139.
    1. Sun Y., Marz P., Otten U., Ge J., Rose-John S. The effect of gp130 stimulation on glutamate-induced excitotoxicity in primary hippocampal neurons. Biochem. Biophys. Res. Commun. 2002;295:532–539.
    1. 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. 2002;22:5516–5524.
    1. Fukada T., Hibi M., Yamanaka Y., Takahashi-Te zuka M., Fujitani Y., Yamaguchi T., Nakajima K., Hirano T. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: Involvement of STAT3 in anti-apoptosis. Immunity. 1996;5:449–460.
    1. Takeda K., Kaisho T., Yoshida N., Takeda J., Kishimoto T., Akira S. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: Generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 1998;161:4652–4660.
    1. Catlett-Falcone R., Landowski T.H., Oshiro M.M., Turkson J., Levitzki A., Savino R., Ciliberto G., Moscinski L., Fernandez-Luna J.L., Nunez G., et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10:105–115. ,
    1. Scheller J., Grötzinger J., Rose-John S. Updating IL-6 classic- and trans-signaling. Signal Transduct. 2006;6:240–259.
    1. Müllberg J., Geib T., Jostock T., Hoischen S.H., Vollmer P., Voltz N., Heinz D., Galle P.R., Klouche M., Rose-John S. IL-6-receptor independent stimulation of human gp130 by viral IL-6. J. Immunol. 2000;164:4672–4677.
    1. Pennica D., Wood W.I., Chien K.R. Cardiotrophin-1: A multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways. Cytokine Growth Factor Rev. 1996;7:81–91.
    1. Turnley A.M., Bartlett P.F. Cytokines that signal through the leukemia inhibitory factor receptor-b complex in the nervous system. J. Neurochem. 2000;74:889–899.
    1. Murphy M., Dutton R., Koblar S., Cheema S., Bartlett P. Cytokines which signal through the LIF receptor and their actions in the nervous system. Prog. Neurobiol. 1997;52:355–378.
    1. Patterson P.H. Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology. Proc. Natl. Acad. Sci. USA. 1994;91:7833–7835.
    1. Anneren C. Tyrosine kinase signalling in embryonic stem cells. Clin. Sci. 2008;115:43–55.
    1. Miao T., Wu D., Zhang Y., Bo X., Subang M.C., Wang P., Richardson P.M. Suppressor of cytokine signaling-3 suppresses the ability of activated signal transducer and activator of transcription-3 to stimulate neurite growth in rat primary sensory neurons. J. Neurosci. 2006;26:9512–9519.
    1. Bareyre F.M., Garzorz N., Lang C., Misgeld T., Buning H., Kerschensteiner M. In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration. Proc. Natl. Acad. Sci. USA. 2011;108:6282–6287.
    1. Boulanger M.J., Chow D.C., Brevnova E.E., Garcia K.C. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003;300:2101–2104.
    1. Lee J.C., Mayer-Proschel M., Rao M.S. Gliogenesis in the central nervous system. Glia. 2000;30:105–121.
    1. Bauer S., Kerr B.J., Patterson P.H. The neuropoietic cytokine family in development plasticity, disease and injury. Nat. Rev. Neurosci. 2007;8:221–232.
    1. Thier M., Hall M., Heath J.K., Pennica D., Weis J. Trophic effects of cardiotrophin-1 and interleukin-11 on rat dorsal root ganglion neurons in vitro. Brain Res. Mol. Brain Res. 1999;64:80–84.
    1. De Melo Reis R.A., Schitine C.S., Köfalvi A., Grade S., Cortes L., Gardino P.F., Malva J.O., de Mello F.G. Functional identification of cell phenotypes differentiating from mice retinal neurospheres using single cell calcium imaging. Cell Mol. Neurobiol. 2011;31:835–846.
    1. Homs J., Ariza L., Pagès G., Udina E., Navarro X., Chillón M., Bosch A. Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration. Gene Ther. 2011;18:622–630.
    1. Bauer S. Cytokine control of adult neural stem cells. Ann. N. Y. Acad. Sci. 2009;1153:48–56.
    1. Scheller J., Chalaris A., Schmidt-Arras D., Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim. Biophys. Acta. 2011;1813:878–888.
    1. Gadient R.A., Otten U. Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development. Brain Res. 1994;637:10–14.
    1. Wagner J.A. Is IL-6 both a cytokine and a neurotrophic factor? J. Exp. Med. 1996;183:2417–2419.
    1. Monje M.L., Toda H., Palmer T.D. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–1765.
    1. Nakanishi M., Niidome T., Matsuda S., Akaike A., Kihara T., Sugimoto H. Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur. J. Neurosci. 2007;25:649–58.
    1. Akaneya Y., Takahashi M., Hatanaka H. Interleukin-1 beta enhances survival and interleukin-6 protects against MPP + neurotoxicity in cultures of fetal rat dopaminergic neurons. Exp. Neurol. 1995;136:44–52.
    1. Hama T., Miyamoto M., Tsukui H., Nishio C., Hatanaka H. Interleukin-6 as a neurotrophic factor for promoting the survival of cultured basal forebrain cholinergic neurons from postnatal rats. Neurosci. Lett. 1989;104:340–344.
    1. Hama T., Kushima Y., Miyamoto M., Kubota M., Takei N., Hatanaka H. Interleukin-6 improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from postnatal, two-week-old rats in cultures. Neuroscience. 1991;40:445–452.
    1. Kushima Y., Hama T., Hatanaka H. Interleukin-6 as a neurotrophic factor for promoting the survival of cultured catecholaminergic neurons in a chemically defined medium from fetal and postnatal rat midbrains. Neurosci. Res. 1992;13:267–280.
    1. Kushima Y., Hatanaka H. Interleukin-6 and leukemia inhibitory factor promote the survival of acetylcholinesterase-positive neurons in culture from embryonic rat spinal cord. Neurosci. Lett. 1992;143:110–114.
    1. Loddick S.A., Turnbull A.V., Rothwell N.J. Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J. Cereb. Blood Flow Metab. 1998;18:176–179.
    1. Matsuda S., Wen T.C., Morita F., Otsuka H., Igase K., Yoshimura H., Sakanaka M. Interleukin-6 prevents ischemia-induced learning disability and neuronal and synaptic loss in gerbils. Neurosci. Lett. 1996;204:109–112.
    1. Toulmond S., Vige X., Fage D., Benavides J. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neurosci. Lett. 1992;144:49–52.
    1. Yamada M., Hatanaka H. Interleukin-6 protects cultured rat hippocampal neurons against glutamate-induced cell death. Brain Res. 1994;643:173–180.
    1. Gadient R.A., Otten U.H. Interleukin-6 (IL-6)—A molecule with both beneficial and destructive potentials. Prog. Neurobiol. 1997;52:379–390.
    1. Ihara S., Iwamatsu A., Fujiyoshi T., Komi A., Yamori T., Fukui Y. Identification of interleukin-6 as a factor that induces neurite outgrowth by PC12 cells primed with NGF. J. Biochem. 1996;120:865–868.
    1. Boulanger L.M. Immune proteins in brain development and synaptic plasticity. Neuron. 2009;64:93–109.
    1. Pickering M., O’Connor J.J. Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog. Brain Res. 2007;163:339–354.
    1. Vitkovic L., Konsman J.P., Bockaert J., Dantzer R., Homburger V., Jacque C. Cytokine signals propagate through the brain. Mol. Psychiatry. 2000;5:604–615.
    1. Viviani B., Gardoni F., Marinovich M. Cytokines and neuronal ion channels in health and disease. Int. Rev. Neurobiol. 2007;82:247–263.
    1. Kahn M.A., De Vellis J. Regulation of an oligodendrocyte progenitor cell line by the interleukin-6 family of cytokines. Glia. 1994;12:87–98.
    1. Valerio A., Ferrario M., Dreano M., Garotta G., Spano P., Pizzi M. Soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro differentiation of purified rat oligodendroglial lineage cells. Mol. Cell Neurosci. 2002;21:602–615.
    1. Zhang P.L., Izrael M., Ainbinder E., Ben-Simchon L., Chebath J., Revel M. Increased myelinating capacity of embryonic stem cell derived oligodendrocyte precursors after treatment by interleukin-6/soluble interleukin-6 receptor fusion protein. Mol. Cell Neurosci. 2006;31:387–398.
    1. Islam O., Gong X., Rose-John S., Heese K. Interleukin-6 and neural stem cells: More than gliogenesis. Mol. Biol. Cell. 2009;20:188–199.
    1. Oh J., McCloskey M.A., Blong C.C., Bendickson L., Nilsen-Hamilton M., Sakaguchi D.S. Astrocyte-derived interleukin-6 promotes specific neuronal differentiation of neural progenitor cells from adult hippocampus. J. Neurosci. Res. 2010;88:2798–2809.
    1. Yang Y.C., Yin T. Inteleukin-11 and its receptor. Biofiictors. 1992;4:15–21.
    1. Du X.X., Williams D.A. Interleukin-11: A multifunctional growth factor derived from the hematopoietic microenvironment. Blood. 1994;83:2023–2030.
    1. Paul S.R., Bennett F., Calvetti J.A., Kelleher K., Wood C.R., OHara R.M., Leary A.C., et al. Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine. Proc. Natl. Acad. Sci. USA. 1990;87:7512–7516.
    1. Rose T.M., Bruce A.G. Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6. Proc. Natl. Acad. Sci. USA. 1991;88:8641–8645.
    1. Hilton D.J. LIF: Lots of interesting functions. Trends Biochem. Sci. 1992;17:72–76.
    1. Kishimoto T., Akira S., Taga T. Interleukin-6 and its receptor: A paradigm for cytokines. Science. 1992;258:593–597.
    1. Davis S., Aldrich T.H., Stahl N., Pan L., Taga T., Kishimoto T., Ip N.Y., Yancopolous G.D. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science. 1993;260:1805–1808.
    1. 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. 2004;11:985–996.
    1. Dowsing B.J., Hayes A., Bennett T.M., Morrison W.A., Messina A. Effects of LIF dose and laminin plus fibronectin on axotomized sciatic nerves. Muscle Nerve. 2000;23:1356–1364.
    1. 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. 1994;37:213–218.
    1. Ikeda K., Iwasaki Y., Shiojima T., Kinoshita M. Neuroprotective effect of various cytokines on developing spinal motoneurons following axotomy. J. Neurol. Sci. 1996;135:109–113.
    1. 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. 1995;18:1344–1347.
    1. 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. 2001;922:144–147.
    1. Bauer S., Patterson P.H. Leukemia inhibitory factor promotes neural stem cell self renewal in the adult brain. J. Neurosci. 2006;26:12089–12099.
    1. Majumder A., Banerjee S., Harrill J.A., Machacek D.W., Mohamad O., Bacanamwo M., Mundy W.R., Wei L., Dhara S.K., Stice S.L. Neurotrophic effects of leukemia inhibitory factor on neural cells derived from human embryonic stem cells. Stem Cells. 2012;30:2387–2399.
    1. 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. 2000;22:86–95.
    1. Buono K.D., Vadlamuri D., Gan Q., Levison S.W. Leukemia inhibitory factor is essential for subventricular zone neural stem cell and progenitor homeostasis as revealed by a novel flow cytometric analysis. Dev. Neurosci. 2012;34:449–462.
    1. Carpenter M.K., Cui X., Hu Z.Y., Jackson J., Sherman S., Seiger A., Wahlberg L.U. In vitro expansion of a multipotent population of human neural progenitor cells. Exp. Neurol. 1999;158:265–278.
    1. Wright L.S., Li J., Caldwell M.A., Wallace K., Johnson J.A., Svendsen C.N. Gene expression in human neural stem cells: Effects of leukemia inhibitory factor. J. Neurochem. 2003;86:179–195.
    1. Pagano S.F., Impagnatiello F., Girelli M., Cova L., Grioni E., Onofri M., Cavallaro M., Etteri S., Vitello F., Giombini S., et al. Isolation and characterization of neural stem cells from the adult human olfactory bulb. Stem Cells. 2000;18:295–300.
    1. Barnabe-Heider F., Wasylnka J.A., Fernandes K.J., Porsche C., Sendtner M., Kaplan D.R., Miller F.D. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron. 2005;48:253–265.
    1. Ishibashi T., Dakin K.A., Stevens B., Lee P.R., Kozlov S.V., Stewart C.L., Fields R.D. Astrocytes promote myelination in response to electrical impulses. Neuron. 2006;49:823–832.
    1. Schmiz T., Chew L.J. Cytokines and myelination in the central nervous system. Sci. World J. 2008;8:1119–1147.
    1. Mitsumoto H., Ikeda K., Klinkosz B., Cedarbaum J.M., Wong V., Lindsay R.M. Arrest of motor neuron disease in wobbler mice cotreated with BDNF and CNTF. Science. 1994;265:1107–1110.
    1. Leibinger M., Müller A., Andreadaki A., Hauk T.G., Kirsch M., Fischer D. Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliaryneurotrophic factor and leukemia inhibitory factor. J. Neurosci. 2009;29:14334–14341.
    1. Butzkueven H., Emery B., Cipriani T., Marriott M.P., Kilpatrick T.J. Endogenous leukemia inhibitory factor production limits autoimmune demyelination and oligodendrocyte loss. Glia. 2006;53:696–703.
    1. White U.A., Stephens J.M. Neuropoietin activates STAT3 independent of LIFR activation in adipocytes. Biochem. Biophys. Res. Commun. 2010;395:48–50.

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