THE P38 RK MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY REGULATES INTERLEUKIN-6 SYNTHESIS IN RESPONSE TO TUMOR-NECROSIS-FACTOR/

Tumour necrosis factor (TNF) is a pleiotropic cytokine, the activities of which include effects on gene expression, cell growth and cell dea th. The biological signalling mechanisms which are responsible for the se TNF effects remain largely unknown. Here we demonstrate that the st ress-responsive p38 mitogen-activated protein (MAP) kinase is involved in TNF-induced cytokine expression. TNF treatment of cells activated the p38 MAP kinase pathway, as revealed by increased phosphorylation o f p38 MAP kinase itself, activation of the substrate protein MAPKAP ki nase-2, and culminating in the phosphorylation of the heat shock prote in 27 (hsp27). Pretreatment of cells with the highly specific p38 MAP kinase inhibitor SB203580 completely blocked this TNF-induced activati on of MAPKAP kinase-2 and hsp27 phosphorylation. Under the same condit ions, SB203580 also completely inhibited TNF-induced synthesis of inte rleukin (IL)-6 and expression of a reporter gene that was driven by a minimal promoter containing two NF-kappa B elements. However, neither TNF-induced DNA binding of NF-kappa B nor TNF-induced phosphorylation of its subunits was modulated by SB203580, suggesting that NF-kappa B is not a direct target for the p38 MAP kinase pathway. Interestingly, TNF-induced cytotoxicity was not affected by SB203580, indicating that p38 MAP kinase might be an interesting target to interfere selectivel y with TNF-induced gene activation.