Biomechanical signals inhibit IKK activity to attenuate NF-κB transcription activity in inflamed Chondrocytes

Objective: While the effects of biomechanical signals in the form of joint movement and exercise are known tob e beneficial to inflamed joints, limited information is available regarding the intracellular mechanisms of their actions. This study was undertaken to examinie the intracellular mechanisms by which biomechanical signals suppress proinflammatory gene induction by the interleukin-1-beta (IL-1 beta)-induced NF-kappa B signaling cascade in articular chondrocytes. Methods. Primary rat articular chondrocytes were exposed to biomechanical signals in the form of cyclic tensile strain, and the effects on the NF-kappa B signaling cascade were examined by Western blot analysis, real-time polymerase chain reaction, and immunofluorescence. Results. Cyclic tensile strain rapidly inhibited the IL-1 beta-induced nuclear translocation of NF-kappa B, but not its IL-1 beta-induced phosphorylation at serine 276 and serine 536, which are necessary for its transactivation and transciptional efficacy, respectively. Examination of upstream events revealed that cyclic tensile strain also inhibited the cytoplasmic protein degradation of I kappa B beta and I kappa B alpha, as well as repressed their gene transcription. Additionally, cyclic tensile strain induced a rapid nuclear translocation of I kappa B alpha to potentially prevent NF kappa B binding to DNA. Furthermore, the inhibition of IL-1 beta-induced degradation of I kappa B by clyclic tensile strain was mediated by down-regulation of I kappa B kinase activity. Conclusion. These results indicate that the signals generated by cyclic tensile strain act at multiple sites within the NF-B signaling cascade to inhibit IL-1 beta-induced proinflammatory gene induction. Taken together, these findings provide insight into how biomechanical signals regulate and reduce inflammation, and underscore their potential in enhancing the ability of chondrocytes to curb inflammation in diseased joints.