Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Laboratory Investigation

Volumn 91, Issue 4, 2011, Pages 609-618

  Yamaguchi, Kanji ^a   Itoh, Yoshito ^a   Yokomizo, Chihiro ^a   Nishimura, Takeshi ^a   Niimi, Toshihisa ^a   Umemura, Atsushi ^a   Fujii, Hideki ^a   Okanoue, Takeshi ^a,b   Yoshikawa, Toshikazu ^a  

^a KYOTO PREFECTURAL UNIVERSITY OF MEDICINE   (Japan)

^b Saiseikai Imperial Gift Foundation Inc Saiseikai Suita Hospital   (Japan)

Author keywords

db db mice; IL 6; IL 6 receptor; MCD diet; NASH; STAT3

Indexed keywords

CHOLINE; FATTY ACID; GLYCOPROTEIN GP 130; IMMUNOGLOBULIN G; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; INTERLEUKIN 6 RECEPTOR NEUTRALIZING ANTIBODY; LEPTIN; MESSENGER RNA; METHIONINE; NEUTRALIZING ANTIBODY; PROTEIN BCL 2; REDOX EFFECTOR FACTOR 1; STAT3 PROTEIN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; CONTROLLED STUDY; DISEASE EXACERBATION; DOWN REGULATION; FATTY ACID BLOOD LEVEL; GENE EXPRESSION; INJURY SEVERITY; LIPID PEROXIDATION; LIVER CELL; LIVER FIBROSIS; LIVER INJURY; LIVER PROTECTION; MALE; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; SIGNAL TRANSDUCTION;

ANIMALS; ANTIBODIES, NEUTRALIZING; APOPTOSIS; CHOLINE DEFICIENCY; DIET; DNA-(APURINIC OR APYRIMIDINIC SITE) LYASE; FATTY LIVER; FIBROSIS; GENE EXPRESSION; HEPATOCYTES; INJECTIONS, INTRAPERITONEAL; INTERLEUKIN-6; LEPTIN; LIVER; MALE; METHIONINE; MICE; MICE, INBRED C57BL; PROTO-ONCOGENE PROTEINS C-BCL-2; RATS; RECEPTORS, INTERLEUKIN-6; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR;

EID: 79953176357     PISSN: 00236837     EISSN: 15300307     Source Type: Journal    
DOI: 10.1038/labinvest.2011.2     Document Type: Article

References (33)

1. Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: mayo clinic experience with a hitherto unnamed disease. Mayo Clinic Proc 1980;55:434-438.
2. Baranova A, Schlauch K, Elariny H, et al. Gene expression patterns in hepatic tissue and visceral adipose tissue of patients with nonalcoholic fatty liver disease. Obes Surg 2007;17:1111-1118. (Pubitemid 350042936)
3. Jarrar MH, Baranova A, Collantes R, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008;27:412-421.
4. Wieckowska A, Papouchado BG, Li Z, et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008;103:1372-1379. (Pubitemid 351813900)
5. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 1996;274:1379-1383. (Pubitemid 26391463)
6. Selzner N, Selzner M, Odermatt B, et al. ICAM-1 triggers liver regeneration through TNF and IL-6 release in mice. Gastroenterology 2003;124:692-700.
7. Febbraio MA. Gp130 receptor ligands as potential therapeutic targets for obesity. J Clin Invest 2007;117:841-849. (Pubitemid 46556736)
8. Inoue H, Ogawa W, Ozaki M, et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med 2004;10:168-174. (Pubitemid 38524887)
9. Klein C, Wü stefeld T, Assmus U, et al. The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. J Clin Invest 2005;115:860-869. (Pubitemid 40489390)
10. Kovalovich K, Li W, DeAngelis R, et al. Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xl. J Biol Chem 2001;276: 26605-26613.
11. Sun Z, Klein AS, Radaeva S, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. Gastroenterology 2003;125:202-215. (Pubitemid 36799120)
12. Jin X, Zhang Z, Beer-Stolz D, et al. Interleukin-6 inhibits oxidative injury and necrosis after extreme liver resection. Hepatology 2007; 46:802-812. (Pubitemid 47436127)
13. Chen H, Charlat O, Tartaglia LA, et al. Evidence that diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996;84:491-495. (Pubitemid 26060722)
14. Sahai A, Malladi P, Pan X, et al. Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol Gastrointest Liver Physiol 2004;287:G1035-G1043. (Pubitemid 39423696)
15. Rinella ME, Elias MS, Smolak RR, et al. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 2008;49:1068-1076.
16. Larter CZ, Yeh MM, Haigh WG, et al. Hepatic free fatty acids accumulate in experimental steatohepatitis: role of adaptive pathways. J Hepatol 2008;48:638-647.
17. Yamaguchi K, Itoh Y, Yokomizo C, et al. Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Lab Invest 2010;90: 1169-1178.
18. Okazaki M, Yamada Y, Nishimoto N, et al. Characterization of antimouse interleukin-6 receptor antibody. Immunol Lett 2002;84: 231-240. (Pubitemid 35292384)
19. Izumi-Nagai K, Nagai N, Ozawa Y, et al. Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization. Am J Pathol 2007;170:2149-2158. (Pubitemid 47339286)
20. Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007;45:1366-1374. (Pubitemid 46918320)
21. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402-408. (Pubitemid 34164012)
22. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008;3:1101-1108. (Pubitemid 351818697)
23. Okada S, Nakamura M, Mikami Y, et al. Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. J Neurosci Res 2004;76:265-276. (Pubitemid 38451214)
24. Uchiyama Y, Yoshida H, Koike N, et al. Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production. Int Immunopharmacol 2008;8: 1595-1601.
25. Day CP, James OF. Steatohepatitis: a tale of two 'hit'? Gastroenterology 1998;114:842-845.
26. Peters M, Blinn G, Jostock T, et al. Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration. Gastroenterology 2000;119:1663-1671. (Pubitemid 32198692)
27. Jin X, Zimmers TA, Perez EA, et al. Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair. Hepatology 2006;43:474-484.
28. Rotter Sopasakis V, Larsson BM, Johansson A, et al. Short-term infusion of interleukin-6 does not induce insulin resistance in vivo or impair insulin signalling in rats. Diabetologia 2004;47:1879-1887. (Pubitemid 40110194)
29. Senn JJ, Klover PJ, Nowak IA, et al. Suppressor of cytokine signaling-3, a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 2003;278:13740-13746. (Pubitemid 36799910)
30. Ueki K, Kondo T, Tseng YH, et al. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci 2004;101: 10422-10427. (Pubitemid 38924941)
31. Bates SH, Stearns WH, Dundon TA, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 2003;421:856-859. (Pubitemid 36254146)
32. Banks AS, Davis SM, Bates SH, et al. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000;275: 14563-14572. (Pubitemid 30339746)
33. Kroy DC, Beraza N, Tschaharganeh DF, et al. Lack of interleukin-6/ glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice. Hepatology 2010;51:463-473.