Gastroenterology
Volume 137, Issue 6 , Pages 2125-2135.e2 , December 2009

Myeloid STAT3 Inhibits T Cell-Mediated Hepatitis by Regulating T Helper 1 Cytokine and Interleukin-17 Production

  • Fouad Lafdil

      Affiliations

    • Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
    • ,
  • Hua Wang

      Affiliations

    • Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
    • ,
  • Ogyi Park

      Affiliations

    • Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
    • ,
  • Weici Zhang

      Affiliations

    • Division of Rheumatology, University of California at Davis, Davis, California
    • ,
  • Yuki Moritoki

      Affiliations

    • Division of Rheumatology, University of California at Davis, Davis, California
    • ,
  • Shi Yin

      Affiliations

    • Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
    • ,
  • Xin Yuan Fu

      Affiliations

    • Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indianapolis, Indiana
    • ,
  • M. Eric Gershwin

      Affiliations

    • Division of Rheumatology, University of California at Davis, Davis, California
    • ,
  • Zhe–Xiong Lian

      Affiliations

    • Division of Rheumatology, University of California at Davis, Davis, California
    • ,
  • Bin Gao

      Affiliations

    • Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
    • Corresponding Author InformationReprint requests Address requests for reprints to: Bin Gao, MD, PhD, Section on Liver Biology, NIAAA/NIH, 5625 Fishers Lane, Bethesda, Maryland 20892

Received 2 June 2009 ,Accepted 6 August 2009.

References 

  1. Chang KM. Immunopathogenesis of hepatitis C virus infection. Clin Liver Dis. 2003;7:89–105
  2. Rehermann B. Intrahepatic T cells in hepatitis B: viral control versus liver cell injury. J Exp Med. 2000;191:1263–1268
  3. Diamantis I, Boumpas DT. Autoimmune hepatitis: evolving concepts. Autoimmun Rev. 2004;3:207–214
  4. He XS, Ansari AA, Ridgway WM, et al. New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. Cell Immunol. 2006;239:1–13
  5. Thiele GM, Freeman TL, Klassen LW. Immunologic mechanisms of alcoholic liver injury. Semin Liver Dis. 2004;24:273–287
  6. Caldwell CC, Tschoep J, Lentsch AB. Lymphocyte function during hepatic ischemia/reperfusion injury. J Leukoc Biol. 2007;82:457–464
  7. Rosen HR. Transplantation immunology: what the clinician needs to know for immunotherapy. Gastroenterology. 2008;134:1789–1801
  8. Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 1992;90:196–203
  9. Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. Z Gastroenterol. 2007;45:63–70
  10. Takeda K, Hayakawa Y, Van Kaer L, et al. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci U S A. 2000;97:5498–5503
  11. Nakashima H, Kinoshita M, Nakashima M, et al. Superoxide produced by Kupffer cells is an essential effector in concanavalin A-induced hepatitis in mice. Hepatology. 2008;48:1979–1988
  12. Bonder CS, Ajuebor MN, Zbytnuik LD, et al. Essential role for neutrophil recruitment to the liver in concanavalin A-induced hepatitis. J Immunol. 2004;172:45–53
  13. Louis H, Le Moine A, Flamand V, et al. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice. Gastroenterology. 2002;122:2001–2010
  14. Jaruga B, Hong F, Sun R, et al. Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes. J Immunol. 2003;171:3233–3244
  15. Hong F, Jaruga B, Kim WH, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J Clin Invest. 2002;110:1503–1513
  16. Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity. 2007;27:647–659
  17. Nagata T, McKinley L, Peschon JJ, et al. Requirement of IL-17RA in Con A induced hepatitis and negative regulation of IL-17 production in mouse T cells. J Immunol. 2008;181:7473–7479
  18. Gantner F, Leist M, Lohse AW, et al. Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor. Hepatology. 1995;21:190–198
  19. Radaeva S, Sun R, Pan HN, et al. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology. 2004;39:1332–1342
  20. Erhardt A, Biburger M, Papadopoulos T, et al. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology. 2007;45:475–485
  21. Sun R, Park O, Horiguchi N, et al. STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice. Hepatology. 2006;44:955–966
  22. Siebler J, Wirtz S, Klein S, et al. A key pathogenic role for the STAT1/T-bet signaling pathway in T cell-mediated liver inflammation. Hepatology. 2003;38:1573–1580
  23. Klein C, Wustefeld 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
  24. Luedde T, Assmus U, Wustefeld T, et al. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J Clin Invest. 2005;115:849–859
  25. Beraza N, Ludde T, Assmus U, et al. Hepatocyte-specific IKK γ/NEMO expression determines the degree of liver injury. Gastroenterology. 2007;132:2504–2517
  26. Maeda S, Chang L, Li ZW, et al. IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα. Immunity. 2003;19:725–737
  27. Sakamori R, Takehara T, Ohnishi C, et al. Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice. Hepatology. 2007;46:1564–1573
  28. Haga S, Terui K, Zhang HQ, et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms. J Clin Invest. 2003;112:989–998
  29. Das M, Sabio G, Jiang F, et al. Induction of hepatitis by JNK-mediated expression of TNF-α. Cell. 2009;136:249–260
  30. Matsukawa A, Kudo S, Maeda T, et al. Stat3 in resident macrophages as a repressor protein of inflammatory response. J Immunol. 2005;175:3354–3359
  31. Chen Z, Laurence A, O'Shea JJ. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin Immunol. 2007;19:400–408
  32. Dong C. Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol Rev. 2008;226:80–86
  33. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28:454–467
  34. Jaruga B, Hong F, Kim WH, et al. IFN-{γ}/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1044–G1052
  35. Geisler F, Algul H, Paxian S, et al. Genetic inactivation of RelA/p65 sensitizes adult mouse hepatocytes to TNF-induced apoptosis in vivo and in vitro. Gastroenterology. 2007;132:2489–2503
  36. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–146
  37. Siebler J, Wirtz S, Frenzel C, et al. Cutting edge: a key pathogenic role of IL-27 in T cell-mediated hepatitis. J Immunol. 2008;180:30–33
  38. Lucas S, Ghilardi N, Li J, et al. IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2003;100:15047–15052
  39. Bender H, Wiesinger MY, Nordhoff C, et al. Interleukin-27 displays interferon-γ-like functions in human hepatoma cells and hepatocytes. Hepatology. 2009;50:585–591
  40. Yoshida H, Miyazaki Y. Interleukin 27 signaling pathways in regulation of immune and autoimmune responses. Int J Biochem Cell Biol. 2008;40:2379–2383
  41. Wolk K, Sabat R. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 2006;17:367–380
  42. Ansel KM, Djuretic I, Tanasa B, et al. Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol. 2006;24:607–656
  43. Zocco MA, Carloni E, Pescatori M, et al. Characterization of gene expression profile in rat Kupffer cells stimulated with IFN-α or IFN-γ. Dig Liver Dis. 2006;38:563–577
  44. Lemmers A, Moreno C, Gustot T, et al. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology. 2009;49:646–657
  45. Witowski J, Pawlaczyk K, Breborowicz A, et al. IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GRO α chemokine from mesothelial cells. J Immunol. 2000;165:5814–5821
  46. Laan M, Cui ZH, Hoshino H, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol. 1999;162:2347–2352
  47. Yu Z, Kone BC. The STAT3 DNA-binding domain mediates interaction with NF-κB p65 and inducible nitric oxide synthase transrepression in mesangial cells. J Am Soc Nephrol. 2004;15:585–591

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by the intramural program of NIAAA, NIH.

PII: S0016-5085(09)01395-X

doi: 10.1053/j.gastro.2009.08.004

Gastroenterology
Volume 137, Issue 6 , Pages 2125-2135.e2 , December 2009

Article Tools

* Image Usage & Resolution