Advertisement

Tissue-Protective Cytokines: Structure and Evolution

  • Pietro Ghezzi
  • Darrell Conklin
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 982)

Abstract

Cytokines are important mediators of host defense and immunity, and were first identified for their role in immunity to infections. It was then found that some of them are pathogenic mediators in inflammatory diseases and much of the emphasis is now on pro-inflammatory cytokines, also in consideration of the fact that TNF inhibitors became effective drugs in chronic inflammatory diseases. The recent studies on the tissue-protective activities of erythropoietin (EPO) led to the term “tissue-protective cytokine.” We discuss here how tissue-protective actions might be common to other cytokines, particularly those of the 4-alpha helical structural superfamily.

Key words

Helical cytokines Hematopoietic cytokines 3D structure Evolution Host defense 

Notes

Acknowledgments

Supported by the European Regional Development Fund, Trans-Channel Neuroscience Network to P.G.

References

  1. 1.
    Read AF, Graham AL, Raberg L (2008) Animal defenses against infectious agents: is damage control more important than pathogen control. PLoS Biol 6(12):e4. doi: 08-PLBI-P-4573 (pii)10.1371/journal.pbio.1000004 PubMedCrossRefGoogle Scholar
  2. 2.
    Medzhitov R, Schneider DS, Soares MP (2012) Disease tolerance as a defense strategy. Science 335(6071):936–941. doi:  335/6071/936 (pii)10.1126/science.1214935 PubMedCrossRefGoogle Scholar
  3. 3.
    Oppenheim JJ (2001) Cytokines: past, present, and future. Int J Hematol 74(1):3–8PubMedCrossRefGoogle Scholar
  4. 4.
    Beutler B, Cerami A (1986) Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature 320(6063):584–588. doi: 10.1038/320584a0 PubMedCrossRefGoogle Scholar
  5. 5.
    Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87(6):2095–2147PubMedGoogle Scholar
  6. 6.
    Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A (2000) Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97(19):10526–10531. doi: 97/19/10526 (pii) PubMedCrossRefGoogle Scholar
  7. 7.
    Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, Viviani B, Marinovich M, Cerami A, Coleman TR, Brines M, Ghezzi P (2003) Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med 198(6):971–975. doi: 10.1084/jem.20021067jem.20021067 (pii) PubMedCrossRefGoogle Scholar
  8. 8.
    Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35(7):1732–1737PubMedCrossRefGoogle Scholar
  9. 9.
    D’Angio CT, Finkelstein JN (2000) Oxygen regulation of gene expression: a study in opposites. Mol Genet Metab 71(1–2):371–380. doi: 10.1006/mgme.2000.3074S1096-7192(00)93074-9 (pii) PubMedCrossRefGoogle Scholar
  10. 10.
    Michiels C, Minet E, Mottet D, Raes M (2002) Regulation of gene expression by oxygen: NF-kappaB and HIF-1, two extremes. Free Radic Biol Med 33(9):1231–1242. doi: S0891584902010456 (pii) PubMedCrossRefGoogle Scholar
  11. 11.
    Haddad JJ, Harb HL (2005) Cytokines and the regulation of hypoxia-inducible factor (HIF)-1alpha. Int Immunopharmacol 5(3):461–483. doi: S1567-5769(04)00380-7 (pii)10.1016/j.intimp.2004.11.009 PubMedCrossRefGoogle Scholar
  12. 12.
    Colgan SP, Taylor CT (2010) Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7(5):281–287. doi: nrgastro.2010.39 (pii)10.1038/nrgastro.2010.39 PubMedCrossRefGoogle Scholar
  13. 13.
    Nizet V, Johnson RS (2009) Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9(9):609–617. doi: nri2607 (pii)10.1038/nri2607 PubMedCrossRefGoogle Scholar
  14. 14.
    Zinkernagel AS, Johnson RS, Nizet V (2007) Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med (Berl) 85(12):1339–1346. doi: 10.1007/s00109-007-0282-2 CrossRefGoogle Scholar
  15. 15.
    Werth N, Beerlage C, Rosenberger C, Yazdi AS, Edelmann M, Amr A, Bernhardt W, von Eiff C, Becker K, Schäfer A, Peschel A, Kempf VAJ (2010) Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens. PLoS ONE 5(7):e11576PubMedCrossRefGoogle Scholar
  16. 16.
    Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819. doi: 10.1146/annurev.immunol.15.1.797 PubMedCrossRefGoogle Scholar
  17. 17.
    Miyajima A, Kitamura T, Harada N, Yokota T, Arai K (1992) Cytokine receptors and signal transduction. Annu Rev Immunol 10:295–331. doi: 10.1146/annurev.iy.10.040192.001455 PubMedCrossRefGoogle Scholar
  18. 18.
    Gewiese-Rabsch J, Drucker C, Malchow S, Scheller J, Rose-John S (1802) Role of IL-6 trans-signaling in CCl4 induced liver damage. Biochim Biophys Acta 11:1054–1061. doi: S0925-4439(10)00160-2 (pii)10.1016/j.bbadis.2010.07.023 Google Scholar
  19. 19.
    Katz A, Chebath J, Friedman J, Revel M (1998) Increased sensitivity of IL-6-deficient mice to carbon tetrachloride hepatotoxicity and protection with an IL-6 receptor-IL-6 chimera. Cytokines Cell Mol Ther 4(4):221–227PubMedGoogle Scholar
  20. 20.
    Schafer KH, Mestres P, Marz P, Rose-John S (1999) The IL-6/sIL-6R fusion protein hyper-IL-6 promotes neurite outgrowth and neuron survival in cultured enteric neurons. J Interferon Cytokine Res 19(5):527–532. doi: 10.1089/107999099313974 PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang PL, Izrael M, Ainbinder E, Ben-Simchon L, Chebath J, Revel M (2006) Increased myelinating capacity of embryonic stem cell derived oligodendrocyte precursors after treatment by interleukin-6/soluble interleukin-6 receptor fusion protein. Mol Cell Neurosci 31(3):387–398. doi: S1044-7431(05)00258-7 (pii)10.1016/j.mcn.2005.10.014 PubMedCrossRefGoogle Scholar
  22. 22.
    An Y, Xiao YB (2007) The preventative role of growth hormone on acute liver injury induced by cardiopulmonary bypass in a rat model. Eur J Cardiothorac Surg 31(6):1037–1043. doi:  S1010-7940(07)00335-1 (pii)10.1016/j.ejcts. 2007.01.077 PubMedCrossRefGoogle Scholar
  23. 23.
    Byts N, Samoylenko A, Fasshauer T, Ivanisevic M, Hennighausen L, Ehrenreich H, Siren AL (2008) Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death Differ 15(4):783–792. doi: cdd20081 (pii)10.1038/cdd.2008.1 PubMedCrossRefGoogle Scholar
  24. 24.
    Isgaard J, Aberg D, Nilsson M (2007) Protective and regenerative effects of the GH/IGF-I axis on the brain. Minerva Endocrinol 32(2):103–113PubMedGoogle Scholar
  25. 25.
    Li RC, Guo SZ, Raccurt M, Moudilou E, Morel G, Brittian KR, Gozal D (2011) Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats. Neuroscience 196:237–250. doi:  S0306-4522(11)00971-7 (pii)10.1016/j.neuroscience.2011.08.029 PubMedCrossRefGoogle Scholar
  26. 26.
    Ling FA, Hui DZ, Ji SM (2007) Protective effect of recombinant human somatotropin on amyloid beta-peptide induced learning and memory deficits in mice. Growth Horm IGF Res 17(4):336–341. doi:  S1096-6374(07)00067-6 (pii)10.1016/j.ghir.2007.04.012 PubMedCrossRefGoogle Scholar
  27. 27.
    Saceda J, Isla A, Santiago S, Morales C, Odene C, Hernandez B, Deniz K (2011) Effect of recombinant human growth hormone on peripheral nerve regeneration: experimental work on the ulnar nerve of the rat. Neurosci Lett 504(2):146–150. doi: S0304-3940(11)01295-X (pii)10.1016/j.neulet.2011.09.020 PubMedCrossRefGoogle Scholar
  28. 28.
    Scheepens A, Sirimanne ES, Breier BH, Clark RG, Gluckman PD, Williams CE (2001) Growth hormone as a neuronal rescue factor during recovery from CNS injury. Neuroscience 104(3):677–687. doi: S0306-4522(01)00109-9 (pii) PubMedCrossRefGoogle Scholar
  29. 29.
    Shin DH, Lee E, Kim JW, Kwon BS, Jung MK, Jee YH, Kim J, Bae SR, Chang YP (2004) Protective effect of growth hormone on neuronal apoptosis after hypoxia-ischemia in the neonatal rat brain. Neurosci Lett 354(1):64–68. doi: S0304394003011571 (pii) PubMedCrossRefGoogle Scholar
  30. 30.
    Yi C, Cao Y, Mao SH, Liu H, Ji LL, Xu SY, Zhang M, Huang Y (2009) Recombinant human growth hormone improves survival and protects against acute lung injury in murine Staphylococcus aureus sepsis. Inflamm Res 58(12):855–862. doi: 10.1007/s00011-009-0056-0 PubMedCrossRefGoogle Scholar
  31. 31.
    Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN (2011) Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex. Blood 118(1):60–68. doi: blood-2011-01-329532 (pii)10.1182/blood-2011-01-329532 PubMedCrossRefGoogle Scholar
  32. 32.
    Urdzikova L, Likavcanova-Masinova K, Vanecek V, Ruzicka J, Sedy J, Sykova E, Jendelova P (2011) Flt3 ligand synergizes with granulocyte-colony-stimulating factor in bone marrow mobilization to improve functional outcome after spinal cord injury in the rat. Cytotherapy 13(9):1090–1104. doi: 10.3109/14653249.2011.575355 PubMedCrossRefGoogle Scholar
  33. 33.
    Brazel CY, Ducceschi MH, Pytowski B, Levison SW (2001) The FLT3 tyrosine kinase receptor inhibits neural stem/progenitor cell proliferation and collaborates with NGF to promote neuronal survival. Mol Cell Neurosci 18(4):381–393. doi: 10.1006/mcne.2001.1033S1044-7431(01)91033-4 (pii) PubMedCrossRefGoogle Scholar
  34. 34.
    Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, Mildner-Rihm C, Martin H, Zeiher AM, Dimmeler S (2003) Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 102(4):1340–1346. doi: 10.1182/blood-2003-01-02232003-01-0223 (pii) PubMedCrossRefGoogle Scholar
  35. 35.
    Farmer DG, Ke B, Shen XD, Kaldas FM, Gao F, Watson MJ, Busuttil RW, Kupiec-Weglinski JW (2011) Interleukin-13 protects mouse intestine from ischemia and reperfusion injury through regulation of innate and adaptive immunity. Transplantation 91(7):737–743. doi: 10.1097/TP.0b013e31820c861a PubMedGoogle Scholar
  36. 36.
    Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, Ongini E (2000) Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci 12(7):2265–2272. doi: ejn090 (pii) PubMedCrossRefGoogle Scholar
  37. 37.
    Bachis A, Colangelo AM, Vicini S, Doe PP, De Bernardi MA, Brooker G, Mocchetti I (2001) Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci 21(9):3104–3112PubMedGoogle Scholar
  38. 38.
    Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 98(7):4044–4049. doi: 10.1073/pnas.051606598051606598 (pii) PubMedCrossRefGoogle Scholar
  39. 39.
    Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412(6847):641–647. doi: 10.1038/3508807435088074 (pii) PubMedCrossRefGoogle Scholar
  40. 40.
    Conklin D (2004) Recognition of the helical cytokine fold. J Comput Biol 11(6):1189–1200. doi: 10.1089/cmb.2004.11.1189 PubMedCrossRefGoogle Scholar
  41. 41.
    Bazan JF (1991) Neuropoietic cytokines in the hematopoietic fold. Neuron 7(2):197–208. doi: 0896-6273(91)90258-2 (pii) PubMedCrossRefGoogle Scholar
  42. 42.
    Stockli KA, Lottspeich F, Sendtner M, Masiakowski P, Carroll P, Gotz R, Lindholm D, Thoenen H (1989) Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor. Nature 342(6252):920–923. doi: 10.1038/342920a0 PubMedCrossRefGoogle Scholar
  43. 43.
    Hill EE, Morea V, Chothia C (2002) Sequence conservation in families whose members have little or no sequence similarity: the four-helical cytokines and cytochromes. J Mol Biol 322(1):205–233. doi: S0022283602006538 (pii) PubMedCrossRefGoogle Scholar
  44. 44.
    Conklin D, Haldeman B, Gao Z (2005) Gene finding for the helical cytokines. Bioinformatics 21(9):1776–1781. doi: bti283 (pii)10.1093/bioinformatics/bti283 PubMedCrossRefGoogle Scholar
  45. 45.
    Eisenberg D, Weiss RM, Terwilliger TC (1984) The hydrophobic moment detects periodicity in protein hydrophobicity. Proc Natl Acad Sci U S A 81(1):140–144PubMedCrossRefGoogle Scholar
  46. 46.
    Fox BA, Sheppard PO, O’Hara PJ (2009) The role of genomic data in the discovery, annotation and evolutionary interpretation of the interferon-lambda family. PLoS One 4(3):e4933. doi: 10.1371/journal.pone.0004933 PubMedCrossRefGoogle Scholar
  47. 47.
    Beck G, Habicht GS (1991) Primitive cytokines: harbingers of vertebrate defense. Immunol Today 12(6):180–183PubMedCrossRefGoogle Scholar
  48. 48.
    Beck G, Habicht GS (1996) Characterization of an IL-6-like molecule from an echinoderm (Asterias forbesi). Cytokine 8(7):507–512. doi: S1043-4666(96)90069-1 (pii)10.1006/cyto.1996.0069 PubMedCrossRefGoogle Scholar
  49. 49.
    Beschin A, Bilej M, Torreele E, De Baetselier P (2001) On the existence of cytokines in invertebrates. Cell Mol Life Sci 58(5–6):801–814PubMedCrossRefGoogle Scholar
  50. 50.
    Reichhart JM, Meister M, Dimarcq JL, Zachary D, Hoffmann D, Ruiz C, Richards G, Hoffmann JA (1992) Insect immunity: developmental and inducible activity of the Drosophila diptericin promoter. EMBO J 11(4):1469–1477PubMedGoogle Scholar
  51. 51.
    Huising MO, Kruiswijk CP, Flik G (2006) Phylogeny and evolution of class-I helical cytokines. J Endocrinol 189(1):1–25. doi: 189/1/1 (pii)10.1677/joe.1.06591 PubMedCrossRefGoogle Scholar
  52. 52.
    Malagoli D, Conklin D, Sacchi S, Mandrioli M, Ottaviani E (2007) A putative helical cytokine functioning in innate immune signalling in Drosophila melanogaster. Biochim Biophys Acta 1770(6):974–978. doi: S0304-4165(07)00057-8 (pii)10.1016/j.bbagen.2007.02.008 PubMedCrossRefGoogle Scholar
  53. 53.
    Liongue C, Ward AC (2007) Evolution of Class I cytokine receptors. BMC Evol Biol 7:120. doi: 1471-2148-7-120 (pii)10.1186/1471-2148-7-120 PubMedCrossRefGoogle Scholar
  54. 54.
    Ostrowski D, Ehrenreich H, Heinrich R (2011) Erythropoietin promotes survival and regeneration of insect neurons in vivo and in vitro. Neuroscience 188:95–108. doi: S0306-4522(11)00550-1 (pii)10.1016/j.neuroscience.2011.05.018 PubMedCrossRefGoogle Scholar
  55. 55.
    Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8(8):495–505PubMedGoogle Scholar
  56. 56.
    Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jahnig P, Herrmann M, Knauth M, Bahr M, Heide W, Wagner A, Schwab S, Reichmann H, Schwendemann G, Dengler R, Kastrup A, Bartels C (2009) Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 40(12):e647–e656. doi: STROKEAHA.109.564872 (pii)10.1161/STROKEAHA.109.564872 PubMedCrossRefGoogle Scholar
  57. 57.
    Ehrenreich H, Kastner A, Weissenborn K, Streeter J, Sperling S, Wang KK, Worthmann H, Hayes RL, Von Ahsen N, Kastrup A, Jeromin A, Herrmann M (2011) Circulating damage marker profiles support a neuroprotective effect of erythropoietin in ischemic stroke patients. Mol Med. doi: molmed.2011.00259 (pii)10.2119/molmed.2011.00259
  58. 58.
    Yip HK, Tsai TH, Lin HS, Chen SF, Sun CK, Leu S, Yuen CM, Tan TY, Lan MY, Liou CW, Lu CH, Chang WN (2011) Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. Crit Care 15(1):R40. doi: cc10002 (pii)10.1186/cc10002 PubMedCrossRefGoogle Scholar
  59. 59.
    Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ (2009) Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 111(1):171–180. doi: 10.3171/2009.3.JNS081332 PubMedCrossRefGoogle Scholar
  60. 60.
    Lauria G, Campanella A, Filippini G, Martini A, Penza P, Maggi L, Antozzi C, Ciano C, Beretta P, Caldiroli D, Ghelma F, Ferrara G, Ghezzi P, Mantegazza R (2009) Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability. Amyotroph Lateral Scler 10(5–6):410–415. doi: 10.3109/17482960902995246(pii)10.3109/17482960902995246 PubMedCrossRefGoogle Scholar
  61. 61.
    Duning T, Schiffbauer H, Warnecke T, Mohammadi S, Floel A, Kolpatzik K, Kugel H, Schneider A, Knecht S, Deppe M, Schabitz WR (2011) G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial. PLoS One 6(3):e17770. doi: 10.1371/journal.pone.0017770 PubMedCrossRefGoogle Scholar
  62. 62.
    Brines M, Patel NS, Villa P, Brines C, Mennini T, De Paola M, Erbayraktar Z, Erbayraktar S, Sepodes B, Thiemermann C, Ghezzi P, Yamin M, Hand CC, Xie QW, Coleman T, Cerami A (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A 105(31):10925–10930. doi: 0805594105 (pii)10.1073/pnas.0805594105 PubMedCrossRefGoogle Scholar
  63. 63.
    Beurrier C, Faideau M, Bennouar KE, Escartin C, Kerkerian-Le Goff L, Bonvento G, Gubellini P (2010) Ciliary neurotrophic factor protects striatal neurons against excitotoxicity by enhancing glial glutamate uptake. PLoS One 5(1):e8550. doi: 10.1371/journal.pone.0008550 PubMedCrossRefGoogle Scholar
  64. 64.
    Toth G, Yang H, Anguelov RA, Vettraino J, Wang Y, Acsadi G (2002) Gene transfer of glial cell-derived neurotrophic factor and cardiotrophin-1 protects PC12 cells from injury: involvement of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase pathways. J Neurosci Res 69(5):622–632PubMedCrossRefGoogle Scholar
  65. 65.
    Iniguez M, Berasain C, Martinez-Ansó E, Bustos M, Fortes P, Pennica D, Avila MA, Js P (2006) Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning. J Exp Med 203(13):2809–2815PubMedCrossRefGoogle Scholar
  66. 66.
    Hara M, Yuasa S, Shimoji K, Onizuka T, Hayashiji N, Ohno Y, Arai T, Hattori F, Kaneda R, Kimura K, Makino S, Sano M, Fukuda K (2011) G-CSF influences mouse skeletal muscle development and regeneration by stimulating myoblast proliferation. J Exp Med 208(4):715–727PubMedCrossRefGoogle Scholar
  67. 67.
    Liu S-P, Lee S-D, Lee H-T, Liu DD, Wang H-J, Liu R-S, Lin S-Z, Shyu W-C (2010) Granulocyte colony-stimulating factor activating HIF-1alpha acts synergistically with erythropoietin to promote tissue plasticity. PLoS ONE 5(4):e10093–e10093PubMedCrossRefGoogle Scholar
  68. 68.
    Ma H, Gong H, Chen Z, Liang Y, Yuan J, Zhang G, Wu J, Ye Y, Yang C, Nakai A, Komuro I, Ge J, Zou Y (2012) Association of Stat3 with HSF1 plays a critical role in G-CSF-induced cardio-protection against ischemia/reperfusion injury. J Mol Cell Cardiol 52(6):1282–1290. doi: S0022-2828(12)00106-X (pii)10.1016/j.yjmcc.2012.02.011 PubMedCrossRefGoogle Scholar
  69. 69.
    Shimoji K, Yuasa S, Onizuka T, Hattori F, Tanaka T, Hara M, Ohno Y, Chen H, Egasgira T, Seki T, Yae K, Koshimizu U, Ogawa S, Fukuda K (2010) G-CSF promotes the proliferation of developing cardiomyocytes in vivo and in derivation from ESCs and iPSCs. Cell Stem Cell 6(3):227–237PubMedCrossRefGoogle Scholar
  70. 70.
    Stratos I, Rotter R, Eipel C, Mittlmeier T, Vollmar B (2007) Granulocyte-colony stimulating factor enhances muscle proliferation and strength following skeletal muscle injury in rats. J Appl Physiol 103(5):1857–1863, Bethesda, MD: 1985PubMedCrossRefGoogle Scholar
  71. 71.
    Tsai RK, Chang CH, Wang HZ (2008) Neuroprotective effects of recombinant human granulocyte colony-stimulating factor (G-CSF) in neurodegeneration after optic nerve crush in rats. Exp Eye Res 87(3):242–250. doi: S0014-4835(08)00168-1 (pii)10.1016/j.exer.2008.06.004 PubMedCrossRefGoogle Scholar
  72. 72.
    Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S (2003) Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34(3):745–751. doi: 10.1161/01.STR.0000057814.70180.1701.STR.0000057814.70180.17 (pii) PubMedCrossRefGoogle Scholar
  73. 73.
    Gibson CL, Bath PM, Murphy SP (2010) G-CSF administration is neuroprotective following transient cerebral ischemia even in the absence of a functional NOS-2 gene. J Cereb Blood Flow Metab 30(4):739–743. doi: jcbfm201012 (pii)10.1038/jcbfm.2010.12 PubMedCrossRefGoogle Scholar
  74. 74.
    Scheepens A, Sirimanne ES, Breier BH, Clark RG, Gluckman PD, Williams CE (2001) Growth hormone as a neuronal rescue factor during recovery from CNS injury. Neuroscience 104(3):677–687PubMedCrossRefGoogle Scholar
  75. 75.
    Hirsch M, Knight J, Tobita M, Soltys J, Panitch H, Mao-Draayer Y (2009) The effect of interferon-(beta) on mouse neural progenitor cell survival and differentiation. Biochem Biophys Res Commun 388:181–186PubMedCrossRefGoogle Scholar
  76. 76.
    Tabira T, Konishi Y, Gallyas F Jr (1995) Neurotrophic effect of hematopoietic cytokines on cholinergic and other neurons in vitro. Int J Dev Neurosci 13(3–4):241–252PubMedCrossRefGoogle Scholar
  77. 77.
    Zambrano A, Otth C, Mujica L, Concha II, Maccioni RB (2007) Interleukin-3 prevents neuronal death induced by amyloid peptide. BMC Neurosci 8:82PubMedCrossRefGoogle Scholar
  78. 78.
    Wen TC, Tanaka J, Peng H, Desaki J, Matsuda S, Maeda N, Fujita H, Sato K, Sakanaka M (1998) Interleukin 3 prevents delayed neuronal death in the hippocampal CA1 field. J Exp Med 188(4):635–649PubMedCrossRefGoogle Scholar
  79. 79.
    Iwasaki Y, Ikeda K, Ichikawa Y, Igarashi O, Iwamoto K, Kinoshita M (2002) Protective effect of interleukin-3 and erythropoietin on motor neuron death after neonatal axotomy. Neurol Res 24(7):643–646PubMedCrossRefGoogle Scholar
  80. 80.
    Kannan Y, Moriyama M, Sugano T, Yamate J, Kuwamura M, Kagaya A, Kiso Y (2000) Neurotrophic action of interleukin 3 and granulocyte-macrophage colony-stimulating factor on murine sympathetic neurons. Neuroimmunomodulation 8(3):132–141. doi: 54273(pii) PubMedCrossRefGoogle Scholar
  81. 81.
    Nishihara T, Ochi M, Sugimoto K, Takahashi H, Yano H, Kumon Y, Ohnishi T, Tanaka J (2011) Subcutaneous injection containing IL-3 and GM-CSF ameliorates stab wound-induced brain injury in rats. Exp Neurol 229(2):507–516. doi: S0014-4886(11)00120-8 (pii)10.1016/j.expneurol.2011.04.006 PubMedCrossRefGoogle Scholar
  82. 82.
    Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T (1993) Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res 609(1–2):29–35PubMedCrossRefGoogle Scholar
  83. 83.
    Aderka D, Le JM, Vilcek J (1989) IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice. J Immunol 143(11):3517–3523PubMedGoogle Scholar
  84. 84.
    Cheng L, Wang J, Li X, Xing Q, Du P, Su L, Wang S (2012) Interleukin-6 Induces Gr-1+CD11b+ myeloid cells to suppress CD8+ T cell-mediated liver injury in mice. PLoS ONE 6(3):e17631CrossRefGoogle Scholar
  85. 85.
    Cotter MA, Gibson TM, Nangle MR, Cameron NE (2010) Effects of interleukin-6 treatment on neurovascular function, nerve perfusion and vascular endothelium in diabetic rats. Diabetes Obes Metab 12(8):689–699PubMedCrossRefGoogle Scholar
  86. 86.
    Camargo CA Jr, Madden JF, Gao W, Selvan RS, Clavien PA (1997) Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology 26(6):1513–1520. doi: S0270913997005375 (pii)10.1002/hep.510260619 PubMedCrossRefGoogle Scholar
  87. 87.
    Toth KG, McKay BR, De Lisio M, Little JP, Tarnopolsky MA, Parise G (2011) IL-6 induced stat3 signalling is associated with the proliferation of human muscle satellite cells following acute muscle damage. PLoS ONE 6(3):e17392–e17392PubMedCrossRefGoogle Scholar
  88. 88.
    El-Assal O, Hong F, Kim W-H, Radaeva S, Gao B (2004) IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cell Mol Immunol 1(3):205–211PubMedGoogle Scholar
  89. 89.
    Zhang P, Chebath J, Lonai P, Revel M (2004) Enhancement of oligodendrocyte differentiation from murine embryonic stem cells by an activator of gp130 signaling. Stem Cells 22(3):344–354PubMedCrossRefGoogle Scholar
  90. 90.
    Cameron NE, Cotter MA (2007) The neurocytokine, interleukin-6, corrects nerve dysfunction in experimental diabetes. Exp Neurol 207(1):23–29PubMedCrossRefGoogle Scholar
  91. 91.
    Zhang P-L, Levy AM, Ben-Simchon L, Haggiag S, Chebath J, Revel M (2007) Induction of neuronal and myelin-related gene expression by IL-6-receptor/IL-6: a study on embryonic dorsal root ganglia cells and isolated Schwann cells. Exp Neurol 208(2):285–296PubMedCrossRefGoogle Scholar
  92. 92.
    Fujita T, Tozaki-Saitoh H, Inoue K (2009) P2Y1 receptor signaling enhances neuroprotection by astrocytes against oxidative stress via IL-6 release in hippocampal cultures. Glia 57(3):244–257PubMedCrossRefGoogle Scholar
  93. 93.
    Kolliputi N, Waxman AB (2009) IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation. Am J Physiol Lung Cell Mol Physiol 297(1):L6–16–L16–16PubMedCrossRefGoogle Scholar
  94. 94.
    Hakkoum D, Stoppini L, Muller D (2007) Interleukin-6 promotes sprouting and functional recovery in lesioned organotypic hippocampal slice cultures. J Neurochem 100(3):747–757. doi: JNC4257 (pii)10.1111/j.1471-4159.2006.04257.x PubMedCrossRefGoogle Scholar
  95. 95.
    Wang X-Q, Peng Y-P, Lu J-H, Cao B-B, Qiu Y-H (2009) Neuroprotection of interleukin-6 against NMDA attack and its signal transduction by JAK and MAPK. Neurosci Lett 450(2):122–126PubMedCrossRefGoogle Scholar
  96. 96.
    Waxman AB, Kolliputi N (2009) IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2-induced Bak interactions with mitofusins. Am J Respir Cell Mol Biol 41(4):385–396PubMedCrossRefGoogle Scholar
  97. 97.
    Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183(6):2627–2634PubMedCrossRefGoogle Scholar
  98. 98.
    Jung JE, Kim GS, Chan PH (2011) Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke. Stroke 42(12):3574–3579. doi: STROKEAHA.111.626648 (pii)10.1161/STROKEAHA.111.626648 PubMedCrossRefGoogle Scholar
  99. 99.
    Yamashita T, Sawamoto K, Suzuki S, Suzuki N, Adachi K, Kawase T, Mihara M, Ohsugi Y, Abe K, Okano H (2005) Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem 94(2):459–468. doi: JNC3227 (pii)10.1111/j.1471-4159.2005.03227.x PubMedCrossRefGoogle Scholar
  100. 100.
    Bansal MB, Kovalovich K, Gupta R, Li W, Agarwal A, Radbill B, Alvarez CE, Safadi R, Fiel MI, Friedman SL, Taub RA (2005) Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression. J Hepatol 42(4):548–556PubMedCrossRefGoogle Scholar
  101. 101.
    Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, Jeong JH, Bach JH, Park DH, Yamada K, Nabeshima T, Yoneda Y, Kim HC (2012) Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med 52(7):1159–1174. doi: S0891-5849(11)01252-4 (pii)10.1016/j.freeradbiomed.2011.12.008 PubMedCrossRefGoogle Scholar
  102. 102.
    Zhang P-L, Izrael M, Ainbinder E, Ben-Simchon L, Chebath J, Revel M (2006) Increased myelinating capacity of embryonic stem cell derived oligodendrocyte precursors after treatment by interleukin-6/soluble interleukin-6 receptor fusion protein. Mol Cell Neurosci 31(3):387–398PubMedCrossRefGoogle Scholar
  103. 103.
    Nishina T, Komazawa-Sakon S, Yanaka S, Piao X, Zheng D-M, Piao J-H, Kojima Y, Yamashina S, Sano E, Putoczki T, Doi T, Ueno T, Ezaki J, Ushio H, Ernst M, Tsumoto K, Okumura K, Nakano H (2012) Interleukin-11 Links Oxidative Stress and Compensatory Proliferation. Sci Signal 5(207):ra5. doi: 10.1126/scisignal.2002056 PubMedCrossRefGoogle Scholar
  104. 104.
    Ikeda K, Iwasaki Y, Tagaya N, Shiojima T, Kinoshita M (1995) Neuroprotective effect of cholinergic differentiation factor/leukemia inhibitory factor on wobbler murine motor neuron disease. Muscle Nerve 18(11):1344–1347PubMedCrossRefGoogle Scholar
  105. 105.
    Bengatta S, Arnould C, Letavernier E, Monge M, de Preneuf HM, Werb Z, Ronco P, Lelongt B (2009) MMP9 and SCF protect from apoptosis in acute kidney injury. J Am Soc Nephrol 20(4):787–797. doi: 20/4/787 (pii)10.1681/ASN.2008050515 PubMedCrossRefGoogle Scholar
  106. 106.
    Dhandapani KM, Wade FM, Wakade C, Mahesh VB, Brann DW (2005) Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFkappaB. J Neurochem 95(1):9–19. doi: JNC3319 (pii)10.1111/j.1471-4159.2005.03319.x PubMedCrossRefGoogle Scholar
  107. 107.
    Simpson K, Hogaboam CM, Kunkel SL, Harrison DJ, Bone-Larson C, Lukacs NW (2003) Stem cell factor attenuates liver damage in a murine model of acetaminophen-induced hepatic injury. Lab Invest 83(2):199–206PubMedGoogle Scholar
  108. 108.
    Penkowa M, Giralt M, Carrasco J, Hadberg H, Hidalgo J (2000) Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice. Glia 32(3):271–285. doi:10.1002/1098-1136(200012)32:3<271::AID-GLIA70>3.0.CO;2-5 (pii)PubMedCrossRefGoogle Scholar
  109. 109.
    Lin ZQ, Kondo T, Ishida Y, Takayasu T, Mukaida N (2003) Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol 73(6):713–721PubMedCrossRefGoogle Scholar
  110. 110.
    Han X, Gilbert S, Groschwitz K, Hogan S, Jurickova I, Trapnell B, Samson C, Gully J (2010) Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury. Gut 59(8):1066–1078. doi: gut.2009.203893 (pii)10.1136/gut.2009.203893 PubMedCrossRefGoogle Scholar
  111. 111.
    Fang Y, Gong SJ, Xu YH, Hambly BD, Bao S (2007) Impaired cutaneous wound healing in granulocyte/macrophage colony-stimulating factor knockout mice. Br J Dermatol 157(3):458–465. doi: BJD7979 (pii)10.1111/j.1365-2133.2007.07979.x PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Pietro Ghezzi
    • 1
  • Darrell Conklin
    • 2
    • 3
  1. 1.Brighton & Sussex Medical SchoolFalmerUK
  2. 2.Department of Computer Science and Artificial IntelligenceUniversity of the Basque Country UPV/EHUSan SebastiánSpain
  3. 3.IKERBASQUE, Basque Foundation for ScienceBilbaoSpain

Personalised recommendations