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.