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J.G. Bode, S. Ludwig, C.A. Correia Freitas, F. Schaper, M. Ruhl, S. Melmed, P.C. Heinrich, D. Häussinger

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 p38MAPKby IL-6 acts as an inhibitory signal on IL-6-mediated activation of STAT and the ?2-macroglobulin promoter. We analyzed the role of MKK6/p38MAPKfor IL-6 signal transduction and transcriptional activation of the suppressor of cytokine signaling (SOCS) 3 promoter. Pretreatment of cells with the p38MAPKspecific inhibitor SB202190 downregulates the induction of SOCS3-mRNA expression by IL-6. Accordingly, overexpression of a constitutively active MKK6 in HepG2 cells enhanced basal activity or IL-6-induced transcriptional activation of a SOCS3 promoter reporter construct, whereas overexpression of a dominant negative mutant of MKK6 downregulated the IL-6-mediated activation of the SOCS3 promoter. These data indicate that p38MAPKactivation is crucial for IL-6-induced SOCS3 expression and downregulation of IL-6-mediated gene induction.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 382, 10/2001
Pages: 1447 - 1453

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