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The pro-inflammatory cytokine interleukin 1 β  (IL-1 β ) induces the synthesis of prostaglandin E 2  by upregulating cyclooxygenase-2 (COX-2) in the synovial tissue of individuals with autoimmune diseases, such as rheumatoid arthritis (RA). IL-1 β -mediated stimulation of NF- κ B and MAPK signaling is important for the pathogenesis of RA; however, crosstalk(s) between NF- κ B and MAPK signaling remains to be understood. In this study, we established a model for IL-1 β -induced synovitis and investigated the role of NF- κ B and MAPK signaling in synovitis. We observed an increase in the mRNA and protein levels of COX-2 and prostaglandin E 2  release in cells treated with IL-1 β . NF- κ B and ERK1/2 inhibitors significantly reduced IL-1 β -induced COX-2 expression. IL-1 β  induced the phosphorylation of canonical NF- κ B complex (p65 and p105) and degradation of I κ B α . IL-1 β  also induced ERK1/2 phosphorylation but did not affect the phosphorylation levels of p38 MAPK and JNK. IL-1 β  failed to induce COX-2 expression in cells transfected with siRNA for p65, p105, ERK1, or ERK2. Notably, NF- κ B inhibitors reduced IL-1 β -induced ERK1/2 phosphorylation; however, the ERK1/2 inhibitor had no effect on the phosphorylation of the canonical NF- κ B complex. Although transcription and translation inhibitors had no effect on IL-1 β -induced ERK1/2 phosphorylation, the silencing of canonical NF- κ B complex in siRNA-transfected fibroblasts prevented IL-1 β -induced phosphorylation of ERK1/2. Taken together, our data indicate the importance of the non-transcriptional/translational activity of canonical NF- κ B in the activation of ERK1/2 signaling involved in the IL-1 β -induced development of autoimmune diseases affecting the synovial tissue, such as RA.

frontiers in immunology

Non-Transcriptional and Translational Function of Canonical NF-κB Signaling in Activating ERK1/2 in IL-1β-Induced COX-2 Expression in Synovial Fibroblasts