Interleukin-1β impairment of transforming growth factor β1 signaling by down-regulation of transforming growth factor β receptor type II and up-regulation of smad7 in human articular Chondrocytes

Objective. Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1 beta (IL-1 beta) and transforming growth factor beta 1 (TGF beta I) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1 beta on TGF1 beta receptor type II (TGF beta RII) regulation and TGF beta 1 responsiveness in human articular chondrocytes. Methods. TGF beta 1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (R-Smad) phosphorylation, TGF beta receptors, and Smad expression were determined by Western blotting and real-time reverse transcription-polymerase chain reaction techniques. Signaling pathways were investigated using specific inhibitors, messenger RNA (mRNA) silencing, and expression vectors. Results. IL-I beta down-regulated TGF beta RII expression at both the protein and mRNA levels and led to inhibition of the TGF beta 1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1 beta strongly stimulated the expression of inhibitory Smad7. TGF beta RII overexpression abolished the loss of TGF01 responsiveness induced by IL-I beta. The decrease in TGF beta RII required de novo protein synthesis and involved both the NF-kappa B and JNK pathways. Conclusion. We demonstrate that IL-I beta impairs TGF beta 1 signaling through down-regulation of TGF beta RII, which is mediated by the p65/NF-kappa B and activator protein 1/JNK pathways, and secondarily through the up-regulation of Smad7. These findings show that there is cross-talk in the signaling of 2 regulatory cytokines involved in inflammation.