Biomechanical signals inhibit IKK activity to attenuate NF‐κB transcription activity in inflamed chondrocytes

Abstract

While the effects of biomechanical signals in the form of joint movement and exercise are known to be beneficial to inflamed joints, limited information is available regarding the intracellular mechanisms of their actions. This study was undertaken to examine the intracellular mechanisms by which biomechanical signals suppress proinflammatory gene induction by the interleukin-1-beta (IL-1beta)-induced NF-kappaB signaling cascade in articular chondrocytes. Primary rat articular chondrocytes were exposed to biomechanical signals in the form of cyclic tensile strain, and the effects on the NF-kappaB signaling cascade were examined by Western blot analysis, real-time polymerase chain reaction, and immunofluorescence. Cyclic tensile strain rapidly inhibited the IL-1beta-induced nuclear translocation of NF-kappaB, but not its IL-1beta-induced phosphorylation at serine 276 and serine 536, which are necessary for its transactivation and transcriptional efficacy, respectively. Examination of upstream events revealed that cyclic tensile strain also inhibited the cytoplasmic protein degradation of IkappaBbeta and IkappaBalpha, as well as repressed their gene transcription. Additionally, cyclic tensile strain induced a rapid nuclear translocation of IkappaBalpha to potentially prevent NF-kappaB binding to DNA. Furthermore, the inhibition of IL-1beta-induced degradation of IkappaB by cyclic tensile strain was mediated by down-regulation of IkappaB kinase activity. These results indicate that the signals generated by cyclic tensile strain act at multiple sites within the NF-kappaB signaling cascade to inhibit IL-1beta-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.