Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: Role of signal transducer and activator of transcription 3

Abstract

Interleukin-22 (IL-22), a recently identified member of the IL-10 family of cytokines that is produced by Th17 and natural killer cells, plays an important role in controlling bacterial infection, homeostasis, and tissue repair. Here, we tested the effect of IL-22 on alcoholinduced liver injury in a murine model of chronic-binge ethanol feeding. Feeding male C57BL/6 mice with a Lieber-DeCarli diet containing 5% ethanol for 10 days, followed by a single dose of ethanol (5 g/kg body weight) by gavage, induces significant fatty liver and liver injury with peak serum levels of approximately 250 IU/L alanine aminotransferase and 420 IU/L aspartate aminotransferase 9 hours after gavage. Moreover, chronic-binge ethanol administration increases expression of hepatic and serum inflammatory cytokines and hepatic oxidative stress. Using this model, we demonstrate that treatment with IL-22 recombinant protein activates hepatic signal transducer and activator of transcription 3 (STAT3) and ameliorates alcoholic fatty liver, liver injury, and hepatic oxidative stress. Administration with IL-22 adenovirus also prevents alcohol-induced steatosis and liver injury. Deletion of STAT3 in hepatocytes abolishes the hepatoprotection provided by IL-22 in alcoholic liver injury. In addition, IL-22 treatment down-regulates the hepatic expression of fatty acid transport protein, but up-regulates several antioxidant, antiapoptotic, and antimicrobial genes. Finally, expression of IL-22 receptor 1 is up-regulated whereas IL-22 is undetectable in the livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. Conclusion: Chronicbinge ethanol feeding may be a useful model to study the early stages of alcoholic liver injury. IL-22 treatment could be a potential therapeutic option to ameliorate alcoholic liver disease, due to its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects with the added benefit of potentially few side effects. (HEPATOLOGY 2010;52:1291-1300

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…The biological effects of IL-22 are mediated through binding to IL-22 receptors and consequent activation of the STAT3 signaling pathway [224] . IL-22 protects against liver injury [226][227][228][229][230][231] , reduces fat accumulation and collagen deposition [231][232][233][234] and promotes liver regeneration [235,236] in rodent models of ALD. The antifibrotic properties of IL-22 depend on the significant increase of STAT-mediated HSC senescence, as demonstrated by the increase of β-galactosidase-positive HSCs in IL-22-treated animals [237] .…”

Serum Concentrations of Th17-Associated Interleukins and Autoimmune Phenomena are Associated with the Degree of Liver Damage in Alcoholic Liver Disease

“…Taking into account potential proinflammatory/ profibrotic activity of IL-22 and its increased activation in ALD, neutralizing this cytokine might reduce hepatic injury. On the other hand, recombinant IL-22 or IL-22-cDNA-gene delivery ameliorated the liver damage in murine models of acute toxic/alcoholic hepatitis [37,31]. F-652, a recombinant fusion protein containing human IL-22 and human immunoglobulin G2 (IgG2)-Fc was lately introduced into clinical trials that are recruiting participants.…”

Alcoholic hepatitis: The pivotal role of Kupffer cells

“…Ethanol induced liver injury was alleviated by treatment with IL-6 [93] . IL-22 is another hepato-protective cytokine that has been found to ameliorate hepatocellular damage in fatty liver as well as acute and chronic alcoholic liver injury [94][95][96][97] . It is believed that both IL-6 and IL-22 share the same pathway, STAT3 mediated hepatoprotection [96] .…”

“…IL-22 is another hepato-protective cytokine that has been found to ameliorate hepatocellular damage in fatty liver as well as acute and chronic alcoholic liver injury [94][95][96][97] . It is believed that both IL-6 and IL-22 share the same pathway, STAT3 mediated hepatoprotection [96] . Another potentially important observation relevant to alcoholic hepatitis is a recently reported finding that the administration of lactate reduced inflammation and organ injury in mice with an immune mediated hepatitis [98] .…”