IL-22 inactivates hepatic stellate cells via downregulation of the TGF-β1/Notch signaling pathway

Abstract

Interleukin-22 (IL-22) inhibits liver fibrosis by inducing hepatic stellate cell (HSC) senescence, primarily through the activation of signal transducer and activator of transcription 3 signaling. However, whether other signaling pathways are involved remains unknown. The present study assessed the regulatory mechanism between IL‑22 and the Notch signaling pathway in vitro. The results revealed that IL‑22 had anti‑proliferative effects on HSC‑T6 cells, and cellular inactivation was reflected by simultaneous inhibition of α‑smooth muscle actin, transforming growth factor-β1 (TGF‑β1), tumor necrosis factor-α and intercellular adhesion molecule 1. Treatment with TGF‑β1 resulted in significant Notch3 upregulation and activation of its downstream effectors Hes family basic helix‑loop‑helix (bHLH) transcription factor (Hes)-1, Hes‑5 and Hes related family BHLH transcription factor with YRPW motif 1. Furthermore, this effect was markedly reversed by further treatment with IL‑22, indicating there may be regulatory cascades of IL‑22/TGF‑β1/Notch signaling in HSC‑T6 cells. The results of the present study demonstrated an inhibitory function of IL‑22 towards Notch signaling in hepatic cells, providing evidence that Notch may serve as a novel target for liver fibrosis.

Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development

“…IL-22 can also activate signal transducer and activator of transcription 3 (STAT3) signaling in HSCs and induce their death by senescence, contributing to resolution of liver fibrosis [105]. At the same time, IL-22 was shown to inactivate HSCs by downregulation of the TGF-β1/Notch signaling pathway in HSCs [106].…”

Chronic inflammation evoked by pathogenic stimulus during carcinogenesis

“…IL-17 seems to have dose-and cell source-dependent inflammatory and pro-fibrotic effect, whereas interleukin 22 (IL-22) was associated with protecting against liver fibrosis through downregulation of the TGF-b1/Notch signaling pathway [194] but being pro-fibrotic in cardiac fibrosis through STAT3/and ERK and IL-17, IL-6, IL-1b, IFN-g, and TNF-a [195] and pro-atherosclerotic [196]. Both, IL-17 and IL-22 are associated with poor prognosis in liver cancer [197], but the exact roles of IL-17 and IL-22 need to be defined in detail in regard to concentration, kind of inflammation, and period of chronic inflammation involved in signaling axis and cell sources.…”

Long noncoding RNA homeobox A11 antisense promotes transforming growth factor β1‑induced fibrogenesis in cardiac fibroblasts

“…TGFβ superfamily ligands bind to the type II receptor and recruit the phosphorylated type I receptor, which then phosphorylates receptor-regulated SMADs, finally forming a complex that accumulates in the nucleus. These ligands then act as transcription factors and participate in the regulation of the expression of target genes, including α-SMA, collagen I and FN (24). In the present study, it was first observed that overexpression of HOXA11-AS upregulated the mRNA and protein levels of TGFβ1, whereas knockdown of HOXA11-AS decreased these levels.…”