Interplay of interleukin‐22 and its binding protein in controlling liver scarring
Interplay of interleukin‐22 and its binding protein in controlling liver scarring
复制标题
作者：
B. Gao
I nterleukin (IL)-22, which was discovered in 2000 as a T-cell-derived cytokine, is probably the only cytokine produced by immune cells (e.g., T helper [Th]17 cells, Th22 cells, activated natural killer [NK] cells, and NKT cells) that does not target immune cells. Instead, IL-22 mainly targets epithelial cells, including hepatocytes in the liver, by binding to IL22R1 and IL-10R2. In 2004, it was demonstrated, for the first time, that IL-22 is a hepatoprotective cytokine that ameliorates hepatocellular damage. Subsequently, the epithelial protective effects of IL-22 were also demonstrated in many other organs, including the pancreas, lung, intestine, and kidneys (see a review and references therein). The hepatoprotective function of IL-22 is mediated by binding to IL-22R1 and IL10R2, followed by activation of signal transducer and activator of transcription 3 (STAT3) and subsequent induction of several antiapoptotic proteins, including B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), and myeloid cell leukemia 1 (Mcl-1; Fig. 1). It was generally accepted that IL-22R1 expression is restricted to cells of epithelial origin, including hepatocytes and liver progenitor cells in the liver, but to our surprise, we found that hepatic stellate cells (HSCs), which are not of epithelial origin, also expressed high levels of IL-22R1. In vitro and in vivo IL-22 treatment induced HSC senescence by induction of suppressor of cytokine signaling 3 (SOCS3) and subsequent stabilization of p53, thereby inhibiting liver fibrosis in a mouse model of CCl4-induced liver fibrosis (Fig. 1). The antifibrotic function of IL-22 was also confirmed in another mouse model of bile duct ligation–induced liver fibrosis. Although the hepatoprotective and antifibrotic effects of IL-22 are well documented in animal models, the functions of IL-22 in the pathogenesis of human liver diseases have not been carefully examined. Several previous studies have reported that serum or hepatic levels of IL-22 were elevated and correlated positively with severity of liver disease in patients with cirrhosis or chronic hepatitis B virus (HBV) infection. In addition, elevated hepatic IL-22 expression was reported to be positively correlated with the number of liver progenitor cells in patients with chronic HBV or hepatitis C virus (HCV) infection, and IL-22 treatment promoted liver progenitor cell proliferation. Collectively, these findings suggest that elevated IL-22 contributes to disease progression or plays a compensatory role in promoting liver repair and regeneration. In this issue of HEPATOLOGY, Sertorio et al. examined IL-22 production by peripheral blood mononuclear cells (PBMCs) in 66 Chinese fishermen infected with Schistosoma japonicum and found that PBMCs from these patients had a greater ability to produce IL-22 with or without schistosome egg stimulation, compared with PBMCs from normal healthy controls. Moreover, IL-22 production by resting and egg-stimulated PBMCs from patients was inversely correlated with degree of liver fibrosis and portal vein diameter, suggesting that IL-22 plays a role in protecting against liver fibrosis during S. japonicum infection. The protective function of IL-22 against schistosomeinduced liver fibrosis is believed to be mediated by promoting liver repair and inducing HSC senescence (Fig. 1). In addition, IL-22 has been shown to contribute to the host defense against intracellular parasite infection through stimulation of antimicrobial effectors and matrix metalloproteinase 9, which may also be involved in the protective action of IL-22 in schistosome-induced liver fibrosis. Furthermore, Sertorio et al. reported that expression of IL-22, IL-22 Abbreviations: AH, alcoholic hepatitis; ALF, acute liver failure; Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma-extra large; DCs, dendritic cells; HBV, hepatitis B virus; HCV, hepatitis C virus; HSCs, hepatic stellate cells; IL, interleukin; IL-22BP, IL-22 binding protein; Mcl-1, myeloid cell leukemia 1; NK, natural killer; PBMCs, peripheral blood mononuclear cells; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; Th, T helper. Received January 2, 2015; accepted January 3, 2015. This work was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. Address reprint requests to: Bin Gao, M.D., Ph.D., Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892. E-mail: bgao@mail.nih.gov: fax: 11-301-480-0257. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27688 Potential conflict of interest: Nothing to report.
