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.
Madhavan
Shashi
S
Biomechanics and Tissue Engineering Laboratory, Section of Oral Biology, Ohio State University, Columbus 43210, USA.
Anghelina
Mirela
M
Sjostrom
Danen
D
Dossumbekova
Anar
A
Guttridge
Denis C
DC
Agarwal
Sudha
S
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001696:Biomechanical Phenomena; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D051550:I-kappa B Kinase / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D053509:Matrix Metalloproteinase 13; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C496318:Nos2 protein, rat