Biomechanical signals suppress TAK1 activation to inhibit NF-kappaB transcriptional activation in fibrochondrocytes.

Exercise/joint mobilization is therapeutic for inflammatory joint diseases like rheumatoid and osteoarthritis, but the mechanisms underlying its actions remain poorly understood. We report that biomechanical signals at low/physiological magnitudes are potent inhibitors of inflammation induced by diverse proinflammatory activators like IL-1beta, TNF-alpha, and lipopolysaccharides, in fibrochondrocytes. These signals exert their anti-inflammatory effects by inhibiting phosphorylation of TAK1, a critical point where signals generated by IL-1beta, TNF-alpha, and LPS converge to initiate NF-kappaB signaling cascade and proinflammatory gene induction. Additionally, biomechanical signals inhibit multiple steps in the IL-1beta-induced proinflammatory cascade downstream of IkappaB kinase activation to regulate IkappaBalpha and IkappaBbeta degradation and synthesis, and promote IkappaBalpha shuttling to export nuclear NF-kappaB and terminate its transcriptional activity. The findings demonstrate that biomechanical forces are but another important signal that uses NF-kappaB pathway to regulate inflammation by switching the molecular activation of discrete molecules involved in proinflammatory gene transcription.