title: Hepatoprotective and anti-fibrotic functions of interleukin-22: therapeutic potential for the treatment of alcoholic liver disease.
abstract: Interleukin-22 (IL-22) plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces by binding to the receptors IL-22R1, which is generally thought to be expressed exclusively in epithelial cells, and IL-10R2. Our laboratory previously demonstrated that IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22R1 and IL-10R2. Recently, we have identified high expression levels of IL-22R1 and IL-10R2 in liver progenitor cells and hepatic stellate cells (HSCs). Overexpression of IL-22 in vivo or treatment with IL-22 in vitro promotes proliferation of liver progenitor cells via a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. IL-22 treatment also prevents HSC apoptosis in vitro and in vivo. Surprisingly, overexpression of IL-22, via either gene targeting or exogenous administration of adenovirus expressing IL-22, reduces liver fibrosis and accelerates the resolution of liver fibrosis during recovery. The anti-fibrotic effects of IL-22 are mediated via the activation of STAT3 in HSCs and subsequent induction of suppressor of cytokine signaling 3, which induces HSC senescence. Taken together, the hepatoprotective, mitogenic, and anti-fibrotic effects of IL-22 are beneficial in ameliorating alcoholic liver injury. Importantly, due to the restricted expression of IL-22R1, IL-22 therapy is expected to have few side effects, thus making IL-22 a potential candidate for treatment of alcoholic liver disease.
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA. xiaonikong@sjtu.edu.cn
authors.forename: Xiaoni
authors.initials: X
authors.lastname: Kong
authors.forename: Dechun
authors.initials: D
authors.lastname: Feng
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mathews
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use*; D008099:Liver / Q000166:cytology; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D058990:Molecular Targeted Therapy; D018123:Receptors, Interleukin / Q000378:metabolism; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C415369:interleukin-22 receptor
keywords: hepatic stellate cells; liver fibrosis; liver progenitor cells; senescence