The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription

In this study we show that activation of p38(MAPK) by IL-6 acts as an inhib itory signal on IL-6-mediated activation of STAT and the alpha (2)-macroglo bulin promoter. We analyzed the role of MKK6/p38(MAPK) for IL-6 signal tran sduction and transcriptional activation of the suppressor of cytokine signa ling (SOCS) 3 promoter. Pretreatment of cells with the p38(MAPK)-specific i nhibitor SB202190 downregulates the induction of SOCS3-mRNA expression by I L-6. Accordingly, overexpression of a constitutively active MKK6 in HepG2 c ells enhanced basal activity or IL-6-induced transcriptional activation of a SOCS3 promoter reporter construct, whereas overexpression of a dominant n egative mutant of MKK6 downregulated the IL-6-mediated activation of the SO CS3 promoter. These data indicate that p38(MAPK)-activation is crucial for IL-6-induced SOCS3 expression and downregulation of IL-6-mediated gene indu ction.