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Mol Med. 1995 July; 1(5): 568–575.
PMCID: PMC2229956

Ciliary neurotrophic factor inhibits brain and peripheral tumor necrosis factor production and, when coadministered with its soluble receptor, protects mice from lipopolysaccharide toxicity.


BACKGROUND: The receptor of ciliary neurotrophic factor (CNTF) contains the signal transduction protein gp130, which is also a component of the receptors of cytokines such as interleukin (IL)-6, leukemia-inhibitory factor (LIF), IL-11, and oncostatin M. This suggests that these cytokines might share common signaling pathways. We previously reported that CNTF augments the levels of corticosterone (CS) and of IL-6 induced by IL-1 and induces the production of the acute-phase protein serum amyloid A (SAA). Since the elevation of serum CS is an important feedback mechanism to limit the synthesis of proinflammatory cytokines, particularly tumor necrosis factor (TNF), we have investigated the effect of CNTF on both TNF production and lipopolysaccharide (LPS) toxicity. MATERIALS AND METHODS: To induce serum TNF levels, LPS was administered to mice at 30 mg/kg i.p. and CNTF was administered as a single dose of 10 micrograms/mouse i.v., either alone or in combination with its soluble receptor sCNTFR alpha at 20 micrograms/mouse. Serum TNF levels were the measured by cytotoxicity on L929 cells. In order to measure the effects of CNTF on LPS-induced TNF production in the brain, mice were injected intracerebroventricularly (i.c.v.) with 2.5 micrograms/kg LPS. Mouse spleen cells cultured for 4 hr with 1 microgram LPS/ml, with or without 10 micrograms CNTF/ml, were also analyzed for TNF production. RESULTS: CNTF, administered either alone or in combination with its soluble receptor, inhibited the induction of serum TNF levels by LPS. This inhibition was also observed in the brain when CNTF and LPS were administered centrally. In vitro, CNTF only marginally affected TNF production by LPS-stimulated mouse splenocytes, but it acted synergistically with dexamethasone (DEX) in inhibiting TNF production. Most importantly, CNTF administered together with sCNTFR alpha protected mice against LPS-induced mortality. CONCLUSIONS: These data suggest that CNTF might act as a protective cytokine against TNF-mediated pathologies both in the brain and in the periphery.

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Selected References

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  • Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol. 1993;9:317–343. [PubMed]
  • Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986 Aug 8;233(4764):652–654. [PubMed]
  • Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7251–7255. [PubMed]
  • Perlstein RS, Mougey EH, Jackson WE, Neta R. Interleukin-1 and interleukin-6 act synergistically to stimulate the release of adrenocorticotropic hormone in vivo. Lymphokine Cytokine Res. 1991 Apr;10(1-2):141–146. [PubMed]
  • Dinarello CA, Cannon JG, Mancilla J, Bishai I, Lees J, Coceani F. Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells. Brain Res. 1991 Oct 25;562(2):199–206. [PubMed]
  • Ip NY, Nye SH, Boulton TG, Davis S, Taga T, Li Y, Birren SJ, Yasukawa K, Kishimoto T, Anderson DJ, et al. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell. 1992 Jun 26;69(7):1121–1132. [PubMed]
  • Pennica D, King KL, Shaw KJ, Luis E, Rullamas J, Luoh SM, Darbonne WC, Knutzon DS, Yen R, Chien KR, et al. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1142–1146. [PubMed]
  • Alexander HR, Wong GG, Doherty GM, Venzon DJ, Fraker DL, Norton JA. Differentiation factor/leukemia inhibitory factor protection against lethal endotoxemia in mice: synergistic effect with interleukin 1 and tumor necrosis factor. J Exp Med. 1992 Apr 1;175(4):1139–1142. [PMC free article] [PubMed]
  • Ulich TR, Fann MJ, Patterson PH, Williams JH, Samal B, Del Castillo J, Yin S, Guo K, Remick DG. Intratracheal injection of LPS and cytokines. V. LPS induces expression of LIF and LIF inhibits acute inflammation. Am J Physiol. 1994 Oct;267(4 Pt 1):L442–L446. [PubMed]
  • Rodriguez M, Pavelko KD, McKinney CW, Leibowitz JL. Recombinant human IL-6 suppresses demyelination in a viral model of multiple sclerosis. J Immunol. 1994 Oct 15;153(8):3811–3821. [PubMed]
  • Aderka D, Le JM, Vilcek J. IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice. J Immunol. 1989 Dec 1;143(11):3517–3523. [PubMed]
  • Baumann H, Wong GG. Hepatocyte-stimulating factor III shares structural and functional identity with leukemia-inhibitory factor. J Immunol. 1989 Aug 15;143(4):1163–1167. [PubMed]
  • Richards CD, Brown TJ, Shoyab M, Baumann H, Gauldie J. Recombinant oncostatin M stimulates the production of acute phase proteins in HepG2 cells and rat primary hepatocytes in vitro. J Immunol. 1992 Mar 15;148(6):1731–1736. [PubMed]
  • Fantuzzi G, Benigni F, Sironi M, Conni M, Carelli M, Cantoni L, Shapiro L, Dinarello CA, Sipe JD, Ghezzi P. Ciliary neurotrophic factor (CNTF) induces serum amyloid A, hypoglycaemia and anorexia, and potentiates IL-1 induced corticosterone and IL-6 production in mice. Cytokine. 1995 Feb;7(2):150–156. [PubMed]
  • Shapiro L, Panayotatos N, Meydani SN, Wu D, Dinarello CA. Ciliary neurotrophic factor combined with soluble receptor inhibits synthesis of proinflammatory cytokines and prostaglandin-E2 in vitro. Exp Cell Res. 1994 Nov;215(1):51–56. [PubMed]
  • Davis S, Aldrich TH, Ip NY, Stahl N, Scherer S, Farruggella T, DiStefano PS, Curtis R, Panayotatos N, Gascan H, et al. Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses. Science. 1993 Mar 19;259(5102):1736–1739. [PubMed]
  • Panayotatos N, Everdeen D, Liten A, Somogyi R, Acheson A. Recombinant human CNTF receptor alpha: production, binding stoichiometry, and characterization of its activity as a diffusible factor. Biochemistry. 1994 May 17;33(19):5813–5818. [PubMed]
  • Mengozzi M, Fantuzzi G, Faggioni R, Marchant A, Goldman M, Orencole S, Clark BD, Sironi M, Benigni F, Ghezzi P. Chlorpromazine specifically inhibits peripheral and brain TNF production, and up-regulates IL-10 production, in mice. Immunology. 1994 Jun;82(2):207–210. [PubMed]
  • Masiakowski P, Liu HX, Radziejewski C, Lottspeich F, Oberthuer W, Wong V, Lindsay RM, Furth ME, Panayotatos N. Recombinant human and rat ciliary neurotrophic factors. J Neurochem. 1991 Sep;57(3):1003–1012. [PubMed]
  • Lipton JM, Macaluso A, Hiltz ME, Catania A. Central administration of the peptide alpha-MSH inhibits inflammation in the skin. Peptides. 1991 Jul-Aug;12(4):795–798. [PubMed]
  • HALEY TJ, MCCORMICK WG. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br J Pharmacol Chemother. 1957 Mar;12(1):12–15. [PubMed]
  • DeLean A, Munson PJ, Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. [PubMed]
  • Aggarwal BB, Kohr WJ, Hass PE, Moffat B, Spencer SA, Henzel WJ, Bringman TS, Nedwin GE, Goeddel DV, Harkins RN. Human tumor necrosis factor. Production, purification, and characterization. J Biol Chem. 1985 Feb 25;260(4):2345–2354. [PubMed]
  • Sipe JD, Gonnerman WA, Loose LD, Knapschaefer G, Xie WJ, Franzblau C. Direct binding enzyme-linked immunosorbent assay (ELISA) for serum amyloid A (SAA). J Immunol Methods. 1989 Dec 20;125(1-2):125–135. [PubMed]
  • Gatti S, Faggioni R, Echtenacher B, Ghezzi P. Role of tumour necrosis factor and reactive oxygen intermediates in lipopolysaccharide-induced pulmonary oedema and lethality. Clin Exp Immunol. 1993 Mar;91(3):456–461. [PubMed]
  • Bertini R, Bianchi M, Ghezzi P. Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med. 1988 May 1;167(5):1708–1712. [PMC free article] [PubMed]
  • Parant M, Le Contel C, Parant F, Chedid L. Influence of endogenous glucocorticoid on endotoxin-induced production of circulating TNF-alpha. Lymphokine Cytokine Res. 1991 Aug;10(4):265–271. [PubMed]
  • Libert C, Brouckaert P, Fiers W. Protection by alpha 1-acid glycoprotein against tumor necrosis factor-induced lethality. J Exp Med. 1994 Oct 1;180(4):1571–1575. [PMC free article] [PubMed]
  • Shainkin-Kestenbaum R, Berlyne G, Zimlichman S, Sorin HR, Nyska M, Danon A. Acute phase protein, serum amyloid A, inhibits IL-1- and TNF-induced fever and hypothalamic PGE2 in mice. Scand J Immunol. 1991 Aug;34(2):179–183. [PubMed]
  • Heremans H, Dillen C, Put W, Van Damme J, Billiau A. Protective effect of anti-interleukin (IL)-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels. Eur J Immunol. 1992 Sep;22(9):2395–2401. [PubMed]
  • Fattori E, Cappelletti M, Costa P, Sellitto C, Cantoni L, Carelli M, Faggioni R, Fantuzzi G, Ghezzi P, Poli V. Defective inflammatory response in interleukin 6-deficient mice. J Exp Med. 1994 Oct 1;180(4):1243–1250. [PMC free article] [PubMed]
  • MacPhee IA, Antoni FA, Mason DW. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med. 1989 Feb 1;169(2):431–445. [PMC free article] [PubMed]
  • Mason D. Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today. 1991 Feb;12(2):57–60. [PubMed]
  • Mayer M, Noble M. N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7496–7500. [PubMed]

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