JNK activation is essential for activation of MEK/ERK signaling in IL-1?-induced COX-2 expression in synovial fibroblasts.

ABSTRACT: The proinflammatory cytokine interleukin 1? (IL-1?) induces prostaglandin E₂ (PGE₂) production via upregulation of cyclooxygenase-2 (COX-2) expression in synovial fibroblasts. This effect of IL-1? is involved in osteoarthritis. We investigated MAPK signaling pathways in IL-1?-induced COX-2 expression in feline synovial fibroblasts. In the presence of MAPK inhibitors, IL-1?-induced COX-2 expression and PGE₂ release were both attenuated. IL-1? induced the phosphorylation of p38, JNK, MEK, and ERK1/2. A JNK inhibitor prevented not only JNK phosphorylation but also MEK and ERK1/2 phosphorylation in IL-1?-stimulated cells, but MEK and ERK1/2 inhibitors had no effect on JNK phosphorylation. A p38 inhibitor prevented p38 phosphorylation, but had no effect on MEK, ERK1/2, and JNK phosphorylation. MEK, ERK1/2, and JNK inhibitors had no effect on p38 phosphorylation. We also observed that in IL-1?-treated cells, phosphorylated MEK, ERK1/2, and JNK were co-precipitated with anti-phospho-MEK, ERK1/2, and JNK antibodies. The silencing of JNK1 in siRNA-transfected fibroblasts prevented IL-1? to induce phosphorylation of MEK and ERK1/2 and COX-2 mRNA expression. These observations suggest that JNK1 phosphorylation is necessary for the activation of the MEK/ERK1/2 pathway and the subsequent COX-2 expression for PGE₂ release, and p38 independently contributes to the IL-1? effect in synovial fibroblasts.

SUBMITTER: Kitanaka T 

PROVIDER: S-EPMC5215076 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature