Interleukin (IL)-22 is known to play a key role in promoting antimicrobial immunity,
inflammation, and tissue repair at barrier surfaces by binding to the receptors, IL-10R2 and
IL-22R1.
IL-22R1 is generally thought to be expressed exclusively in epithelial cells. In this study, we identified high levels of IL-10R2 and
IL-22R1 expression on hepatic stellate cells (HSCs), the predominant cell type involved in liver fibrogenesis in response to liver damage. In vitro treatment with
IL-22 induced the activation of signal transducer and activator of transcription (STAT) 3 in primary mouse and human HSCs.
IL-22 administration prevented HSC apoptosis in vitro and in vivo, but surprisingly, the overexpression of
IL-22 by either gene targeting (e.g., IL-22 transgenic mice) or exogenous administration of adenovirus expressing
IL-22 reduced
liver fibrosis and accelerated the resolution of
liver fibrosis during recovery. Furthermore,
IL-22 overexpression or treatment increased the number of senescence-associated
beta-galactosidase-positive HSCs and decreased alpha-smooth muscle actin expression in fibrotic livers in vivo and cultured HSCs in vitro. Deletion of STAT3 prevented IL-22-induced HSC senescence in vitro, whereas the overexpression of a constitutively activated form of STAT3 promoted HSC senescence through p53- and p21-dependent pathways. Finally,
IL-22 treatment up-regulated the suppressor of
cytokine signaling (SOCS) 3 expression in HSCs. Immunoprecipitation analyses revealed that SOCS3 bound p53 and subsequently increased the expression of p53 and its target genes, contributing to IL-22-mediated HSC senescence.
CONCLUSION:
IL-22 induces the senescence of HSCs, which express both IL-10R2 and
IL-22R1, thereby ameliorating liver fibrogenesis. The antifibrotic effect of
IL-22 is likely mediated by the induction of HSC senescence, in addition to the previously discovered hepatoprotective functions of
IL-22.