Effect of interleukin-22 on hepatic stellate cell activation and its mechanism

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Effect of interleukin-22 on hepatic stellate cell activation and its mechanism

Journal Title: Journal of Clinical Hepatology - Year 2024, Vol 40, Issue 11

Abstract

[Objective] To investigate the effect of interleukin-22 （IL-22） on the activation of hepatic stellate cells （HSCs） and its mechanism. [Methods] The human HSC LX-2 cells were selected for the study， and the LX-2 cells induced by TGF-β1 were used to establish a model of HSC activation. LX-2 cells were treated with IL-22 at gradient concentrations， and Western blot and qRT-PCR were used to measure the expression levels of the activation markers COL1A1 and α-SMA and determine the appropriate working concentration and time of the drug. Western blot， qRT-PCR， and immunofluorescence assay were used to determine the levels of Fn14 and the markers for endoplasmic reticulum stress （ERS） and activation in activated HSCs treated by IL-22. ERS in LX-2 cells was induced by tunicamycin （TM）， and Western blot and qRT-PCR were used to measure the levels of markers for ERS and activation in LX-2 cells treated by IL-22. TNF-like weak inducer of apoptosis （TWEAK） and small interfering RNA were used to upregulate and downregulate Fn14， and then the mRNA and protein expression levels of p-IRE1α， IRE1α， XBP1s， COL1A1， and α-SMA were measured. After LX-2 cells induced by TGF-β1 were treated by IL-22， TWEAK was used to upregulate Fn14， and Western blot and immunofluorescence assay were used to measure the levels of Fn14 and the markers for ERS and activation. The independent-samples t-test was used for comparison of continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the Sidak’s multiple comparison test was used for further comparison between two groups. [Results] Compared with the TGF-β1 group， the TGF-β1+IL-22 group had significant reductions in the protein and mRNA expression levels of COL1A1 and α-SMA， with a more significant effect after treatment with 10 ng/mL IL-22 for 24 hours （all P<0.01）. Compared with the TGF-β1 group， the TGF-β1+IL-22 group had significant reductions in the expression levels of Fn14， p-IRE1α， and XBP1s （all P<0.05）. Compared with the TM group， the TM+IL-22 group had significant reductions in the expression levels of p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.05）. Compared with the silenced control group， the Fn14 siRNA group had significant reductions in the expression levels of p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.05）. Compared with the normal control group， the TWEAK group had significant increases in the expression levels of Fn14， p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.01）. Compared with the TGFβ1+IL-22 group， the TGF-β1+IL-22+TWEAK group had significant increases in the expression levels of Fn14， p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.05）. [Conclusion] IL-22 negatively regulates ERS in HSCs by inhibiting Fn14， thereby inhibiting the activation of HSCs.

Authors and Affiliations

Jun GAO, Huan CHEN, Yan LIU, Feng ZHANG, Yuzheng ZHUGE

Keywords

Hepatic Fibrosis Interleukin-22 Hepatic Stellate Cells Endoplasmic Reticulum Stress

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EP ID EP753499
DOI 10.12449/JCH241116
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