AUTHOR=Nakano Rei , Kitanaka Taku , Namba Shinichi , Kitanaka Nanako , Suwabe Yoko , Konno Tadayoshi , Yamazaki Jun , Nakayama Tomohiro , Sugiya Hiroshi 

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

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.579266

DOI=10.3389/fimmu.2020.579266

ISSN=1664-3224

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