全反式维A酸通过AKT和ERK1/2通路影响IL-22诱导HaCaT细胞中的Cx43和GJIC功能

All-trans Retinoic Acid Restores the IL-22-induced Downregulation of Cx43 Expression and Gap Junctional Intercellular Communication by Activating the AKT and ERK1/2 Pathways in HaCaT Cells

目的探索全反式维A酸(RA)通过丝裂原活化蛋白激酶(MAPK)信号通路对IL-22诱导的HaCaT细胞中Cx43表达下调和细胞间隙连接通讯(GJIC)降低的影响。方法应用细胞划痕试验(SLDT)记录RA、IL-22和信号通路抑制剂处理的HaCaT细胞中GJIC的变化。Western blot检测Cx43、p-JNK、p-AKT、p-p38、p-ERK1/2蛋白表达。结果RA以剂量依赖性方式显著增加GJIC功能,并恢复IL-22诱导的HaCaT细胞GJIC功能降低程度。RA显著恢复了IL-22诱导的HaCaT细胞中Cx43表达的下调,但这种作用并非通过抑制IL-22激活的JNK信号通路而发生。RA通过激活AKT和ERK1/2信号通路而不是p38信号通路来抑制IL-22诱导的GJIC降低和Cx43表达下调。此外,研究用AKT抑制剂MK-2206或ERK1/2抑制剂SCH772984处理细胞后显示出相反的结果。结论RA可抑制IL-22诱导的HaCaT细胞Cx43表达下调和GJIC功能降低,且是通过激活AKT和ERK1/2信号通路而不是JNK和p38信号通路介导的。本研究进一步拓展了维A酸在GJIC中作用的理解,并可能为银屑病的治疗提供新的靶点。

Ojective To investigate the effect of all-tvans retinoic acid(RA) on IL-22-induced downregulation of Cx43 expression and decrease of gap junction intercellular communication(GJIC) in HaCaT cells through mitogen-activated protein kinase(MAPK) signaling pathways.Methods The changes of GJIC in HaCaT cells treated with RA, IL-22 and/or signaling pathway inhibitors were recorded by scrape-loading dye-transfer(SLDT) assay. The expression of Cx43, p-JNK, p-AKT, p-p38, and p-ERK1/2 protein was detected by Western blot.Results RA significantly increased GJIC in dose-dependent manners and restored IL-22-induced decrease of GJIC in HaCaT cells. RA significantly restored IL-22-induced downregulation of Cx43 expression in HaCaT cells, but this effect did not occur through the inhibition of IL-22-activated JNK signaling pathway.RA restored IL-22-induced GJIC reduction and Cx43 expression downregulation by activating the AKT and ERK1/2 signaling pathways but not the p38 signaling pathway. Moreover, treatment of HaCaT cells with the AKT inhibitor MK-2206 or ERK1/2 inhibitor SCH772984 showed the opposite results.Conclusion This study suggests that RA restores IL-22-induced downregulation of Cx43 expression and decrease of GJIC in HaCaT cells, which is mediated by activation of the AKT and ERK1/2 signaling pathways but not the JNK and p38 signaling pathways. These findings further expand our understanding of the role of retinoic acid in GJIC and may provide new targets for the treatment of psoriasis.