Abstract

Cytokines, including interleukin-10 (IL-10), are cell signaling molecules taking part in cell‑to‑cell communication, cell proliferation, differentiation, migration and apoptosis. Cytokines also have the ability to induce, regulate, and inhibit inflammation. Cytokines are produced mainly by activated peripheral immune cells, but due to dissemination of the concept of the central nervous system as an immunologically specialized zone, it is considered that cytokine signaling is one of the components of the immune system which can modulate brain functioning. IL-10 shows immunosuppressive properties, and since expression of this cytokine has been shown in the central nervous system, researchers have started to investigate the therapeutic possibilities of IL-10 action in the context of neurodegenerative diseases, which may involve neuroinflammation in their pathogenesis. Recent studies using cell cultures or animal models of neurodegenerative disorders have shown that the importance of IL-10 in the central nervous system goes beyond the anti-inflammatory activity of this cytokine. Involvement of IL-10 in neuroprotection, neurogenesis, regulation of the stress response and hippocampal synaptic plasticity connected with learning and memory is suggested.

References

• 1. Aloisi F., De Simone R., Columba-Cabezas S., Levi G.: Opposite effectsof interferon-gamma and prostaglandin E2 on tumor necrosisfactor and interleukin-10 production in microglia: a regulatory loopcontrolling microglia pro- and anti-inflammatory activities. J. Neurosci.Res., 1999, 56: 571-580
  Google Scholar
• 2. Avital A., Goshen I., Kamsler A., Segal M., Iverfeldt K., Richter–Levin G., Yirmiya R.: Impaired interleukin-1 signaling is associatedwith deficits in hippocampal memory processes and neural plasticity.Hippocampus, 2003, 13: 826-834
  Google Scholar
• 3. Bachis A., Colangelo A.M., Vicini S., Doe P.P., De Bernardi M.A.,Brooker G., Mocchetti I.: Interleukin-10 prevents glutamate-mediatedcerebellar granule cell death by blocking caspase-3-like activity.J. Neurosci., 2001, 21: 3104-3112
  Google Scholar
• 4. Balasingam V., Yong V.W.: Attenuation of astroglial reactivityby interleukin-10. J. Neurosci., 1996, 16: 2945-2955
  Google Scholar
• 5. Banks W.A., Kastin A.J., Broadwell R.D.: Passage of cytokines acrossthe blood-brain barrier. Neuroimmunomodulation, 1995, 2: 241-248
  Google Scholar
• 6. Bluthé R.M., Michaud B., Kelley K.W., Dantzer R.: Vagotomy blocksbehavioural effects of interleukin-1 injected via the intraperitonealroute but not via other systemic routes. Neuroreport, 1996,7: 2823-2827
  Google Scholar
• 7. Briscoe J., Guschin D., Rogers N.C., Watling D., Müller M., Horn F.,Heinrich P., Stark G.R., Kerr I.M.: JAKs, STATs and signal transductionin response to the interferons and other cytokines. Philos. Trans. R.Soc. Lond. B Biol. Sci., 1996, 351: 167-171
  Google Scholar
• 8. Butti E., Cusimano M., Bacigaluppi M., Martino G.: Neurogenicand non-neurogenic functions of endogenous neural stem cells.Front. Neurosci., 2014, 8: 92
  Google Scholar
• 9. Byrnes A.P., MacLaren R.E., Charlton H.M.: Immunological instabilityof persistent adenovirus vectors in the brain: peripheralexposure to vector leads to renewed inflammation, reduced geneexpression, and demyelination. J. Neurosci., 1996, 16: 3045-3055 10 Carson M.J., Doose J.M., Melchior B., Schmid C.D., Ploix C.C.:CNS immune privilege: hiding in plain sight. Immunol. Rev., 2006,213: 48-65
  Google Scholar
• 10. directly protects cortical neurons by activating PI-3 kinase andSTAT-3 pathways. Brain Res., 2011, 1373: 189-194
  Google Scholar
• 11. Fiorentino D.F., Bond M.W., Mosmann T.R.: Two types of mouseT helper cell. IV. Th2 clones secrete a factor that inhibits cytokineproduction by Th1 clones. J. Exp. Med., 1989, 170: 2081-2095
  Google Scholar
• 12. Fleshner M., Goehler L.E., Hermann J., Relton J.K., Maier S.F.,Watkins L.R.: Interleukin-1β induced corticosterone elevation andhypothalamic NE depletion is vagally mediated. Brain Res. Bull.,1995, 37: 605-610
  Google Scholar
• 13. Fouda A.Y., Kozak A., Alhusban A., Switzer J.A., Fagan S.C.: Anti–inflammatory IL-10 is upregulated in both hemispheres after experimentalischemic stroke: hypertension blunts the response. Exp.Transl. Stroke Med., 2013, 5: 12
  Google Scholar
• 14. Francis J., Zhang Z.H., Weiss R.M., Felder R.B.: Neural regulationof the proinflammatory cytokine response to acute myocardial infarction.Am. J. Physiol. Heart Circ. Physiol., 2004, 287: H791-H797
  Google Scholar
• 15. Goshen I., Avital A., Kreisel T., Licht T., Segal M., YirmiyaR.: Environmental enrichment restores memory functioning inmice with impaired IL-1 signaling via reinstatement of long-termpotentiation and spine size enlargement. J. Neurosci., 2009, 29:3395-3403
  Google Scholar
• 16. Goshen I., Kreisel T., Ounallah-Saad H., Renbaum P., Zalzstein Y.,Ben-Hur T., Levy-Lahad E., Yirmiya R.: A dual role for interleukin-1in hippocampal-dependent memory processes. Psychoneuroendocrinology,2007, 32: 1106-1115
  Google Scholar
• 17. Gutierrez E.G., Banks W.A., Kastin A.J.: Murine tumor necrosisfactor alpha is transported from blood to brain in the mouse. J. Neuroimmunol.,1993, 47: 169-176
  Google Scholar
• 18. Holman D.W., Klein R.S., Ransohoff R.M.: The blood-brain barrier,chemokines and multiple sclerosis. Biochim. Biophys. Acta,2011, 1812: 220-230
  Google Scholar
• 19. Hosoi T., Okuma Y., Nomura Y.: Electrical stimulation of afferentvagus nerve induces IL-1β expression in the brain and activatesHPA axis. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2000,279: R141-Rr147
  Google Scholar
• 20. Johnston G.R., Webster N.R.: Cytokines and the immunomodulatoryfunction of the vagus nerve. Br. J. Anaesth., 2009, 102: 453-462
  Google Scholar
• 21. Kamimura D., Yamada M., Harada M., Sabharwal L., Meng J.,Bando H., Ogura H., Atsumi T., Arima Y., Murakami M.: The gatewaytheory: bridging neural and immune interactions in the CNS. Front.Neurosci., 2013, 7: 204
  Google Scholar
• 22. Kelly A., Lynch A., Vereker E., Nolan Y., Queenan P., WhittakerE., O’Neill L.A., Lynch M.A.: The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1β on long termpotentiation. A role for JNK. J. Biol. Chem., 2001, 276: 45564-45572
  Google Scholar
• 23. Ledeboer A., Brevé J.J., Poole S., Tilders F.J., Van Dam A.M.: Interleukin-10,interleukin-4, and transforming growth factor-β differentiallyregulate lipopolysaccharide-induced production of pro-inflammatorycytokines and nitric oxide in co-cultures of rat astroglialand microglial cells. Glia, 2000, 30: 134-142
  Google Scholar
• 24. Lee T.S., Chau L.Y.: Heme oxygenase-1 mediates the anti-inflammatoryeffect of interleukin-10 in mice. Nat. Med., 2002, 8: 240-246
  Google Scholar
• 25. Lee Y.B., Nagai A., Kim S.U.: Cytokines, chemokines, and cytokinereceptors in human microglia. J. Neurosci. Res., 2002, 69: 94-103
  Google Scholar
• 26. Lim S.H., Park E., You B., Jung Y., Park A.R., Park S.G., Lee J.R.:Neuronal synapse formation induced by microglia and interleukin 10 PLoS One, 2013, 8: e81218
  Google Scholar
• 27. McCusker R.H., Kelley K.W.: Immune-neural connections: howthe immune system’s response to infectious agents influences behavior.J. Exp. Biol., 2013, 216: 84-98
  Google Scholar
• 28. Mizuno T., Sawada M., Marunouchi T., Suzumura A.: Productionof interleukin-10 by mouse glial cells in culture. Biochem. Biophys.Res. Commun., 1994, 205: 1907-1915
  Google Scholar
• 29. Molina-Holgado E., Vela J.M., Arévalo-Martín A., Guaza C.: LPS/IFN-γ cytotoxicity in oligodendroglial cells: role of nitric oxide andprotection by the anti-inflammatory cytokine IL-10. Eur. J. Neurosci.,2001, 13: 493-502
  Google Scholar
• 30. Moore K.W., Vieira P., Fiorentino D.F., Trounstine M.L., KhanT.A., Mosmann T.R.: Homology of cytokine synthesis inhibitory factor(IL-10) to the Epstein-Barr virus gene BCRFI. Science, 1990, 248:1230-1234
  Google Scholar
• 31. Niciu M.J., Kelmendi B., Sanacora G.: Overview of glutamatergicneurotransmission in the nervous system. Pharmacol. Biochem.Behav., 2012, 100: 656-664
  Google Scholar
• 32. Otterbein L.E., Bach F.H., Alam J., Soares M., Tao Lu H., WyskM., Davis R.J., Flavell R.A., Choi A.M.: Carbon monoxide has anti-inflammatoryeffects involving the mitogen-activated protein kinasepathway. Nat. Med., 2000, 6: 422-428
  Google Scholar
• 33. Pang Y., Rodts-Palenik S., Cai Z., Bennett W.A., Rhodes P.G.: Suppressionof glial activation is involved in the protection of IL-10 onmaternal E. coli induced neonatal white matter injury. Brain Res.Dev. Brain Res., 2005, 157: 141-149
  Google Scholar
• 34. Park D.S., Stefanis L., Yan C.Y., Farinelli S.E., Greene L.A.: Orderingthe cell death pathway. Differential effects of BCL2, an interleukin-1-convertingenzyme family protease inhibitor, and othersurvival agents on JNK activation in serum/nerve growth factor–deprived PC12 cells. J. Biol. Chem., 1996, 271: 21898-21905
  Google Scholar
• 35. Penn I.: Immunologically privileged brain sites. JAMA, 1972,221: 1412
  Google Scholar
• 36. Perez-Asensio F.J., Perpiñá U., Planas A.M., Pozas E.: Interleukin-10regulates progenitor differentiation and modulates neurogenesisin adult brain. J. Cell Sci., 2013, 126: 4208-4219
  Google Scholar
• 37. Piser T.M.: Linking the cytokine and neurocircuitry hypothesesof depression: a translational framework for discovery and developmentof novel anti-depressants. Brain Behav. Immun., 2010;24: 515-524
  Google Scholar
• 38. Ransohoff R.M., Brown M.A.: Innate immunity in the centralnervous system. J. Clin. Invest., 2012, 122: 1164-1171
  Google Scholar
• 39. Sawada M., Suzumura A., Hosoya H., Marunouchi T., Nagatsu T.:Interleukin-10 inhibits both production of cytokines and expressionof cytokine receptors in microglia. J. Neurochem., 1999, 72: 1466-1471
  Google Scholar
• 40. Seo D.R., Kim K.Y., Lee Y.B.: Interleukin-10 expression in lipopolysaccharide-activatedmicroglia is mediated by extracellular ATP inan autocrine fashion. Neuroreport, 2004, 15: 1157-1161
  Google Scholar
• 41. Sharma S., Yang B., Xi X., Grotta J.C., Aronowski J., Savitz S.I.: IL-
  Google Scholar
• 42. Smith E.M., Cadet P., Stefano G.B., Opp M.R., Hughes T.K.Jr.:IL-10 as a mediator in the HPA axis and brain. J. Neuroimmunol.,1999, 100: 140-148
  Google Scholar
• 43. Strle K., Zhou J.H., Shen W.H., Broussard S.R., Johnson R.W.,Freund G.G., Dantzer R., Kelley K.W.: Interleukin-10 in the brain.Crit. Rev. Immunol., 2001, 21: 427-449
  Google Scholar
• 44. Takeshita Y., Ransohoff R.M.: Inflammatory cell traffickingacross the blood-brain barrier: chemokine regulation and in vitromodels. Immunol. Rev., 2012, 248: 228-239
  Google Scholar
• 45. Tracey K.J.: The inflammatory reflex. Nature, 2002, 420: 853-859
  Google Scholar
• 46. Wilson E.H., Weninger W., Hunter C.A.: Trafficking of immunecells in the central nervous system. J. Clin. Invest., 2010, 120:1368-1379
  Google Scholar
• 47. Wong A.D., Ye M., Levy A.F., Rothstein J.D., Bergles D.E., SearsonP.C.: The blood-brain barrier: an engineering perspective. Front.Neuroeng., 2013, 6: 7
  Google Scholar
• 48. Wong M.L., Bongiorno P.B., Rettori V., McCann S.M., Licinio J.:Interleukin (IL) 1β, IL-1 receptor antagonist, IL-10, and IL-13 geneexpression in the central nervous system and anterior pituitary duringsystemic inflammation: pathophysiological implications. Proc.Natl. Acad. Sci. USA, 1997, 94: 227-232
  Google Scholar
• 49. Wrona D.: Neural-immune interactions: an integrative view ofthe bidirectional relationship between the brain and immune systems.J. Neuroimmunol., 2006, 172: 38-58
  Google Scholar
• 50. Yang J., Jiang Z., Fitzgerald D.C., Ma C., Yu S., Li H., Zhao Z., Li Y.,Ciric B., Curtis M., Rostami A., Zhang G.X.: Adult neural stem cellsexpressing IL-10 confer potent immunomodulation and remyelinationin experimental autoimmune encephalitis. J. Clin. Invest.,2009, 119: 3678-3691
  Google Scholar
• 51. Yirmiya R., Goshen I.: Immune modulation of learning, memory,neural plasticity and neurogenesis. Brain Behav. Immun., 2011,25: 181-213
  Google Scholar
• 52. Zhou Z., Peng X., Insolera R., Fink D.J., Mata M.: Interleukin-10provides direct trophic support to neurons. J. Neurochem., 2009,110: 1617-1627
  Google Scholar

Full text