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.

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…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] . Data showing elevated IL-22 expression in ALD patients suggest that IL-22 administration might be an ideal therapy for alcoholic liver injury [238] . Inhibition of hepatocyte apoptosis was recently suggested as an alternative and attractive approach to reduce liver inflammation during alcohol consumption.…”

Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

“…IL-22 signals to hepatocytes via its heterodimeric receptor complex of IL-22 receptor alpha 1 (IL-22Ra1) and IL-10R2 and can lead to signal transduction via STAT3 (20,21). , and liver injury scores (E).…”

Stellate Cells in Alcoholic Hepatitis

“…Another therapeutic approach is to target IL22 because HSC express high levels of IL22 receptor R1 (IL22R1). In vitro or in vivo treatment with IL22 ameliorates ethanol-induced injury by activating STAT3 in HSC and inducing SOCS3 to stimulate the senescence of HSCs [82,83]. As a final example, activated NK cells are an important cellular pathway for killing activated HSCs via the release of TRAIL [1].…”