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‐1β (IL‐1β) and transforming growth factor β1 (TGFβ1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL‐1β on TGFβ receptor type II (TGFβRII) regulation and TGFβ1 responsiveness in human articular chondrocytes. Methods TGFβ1‐induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP‐Lux induction. Receptor‐activated Smad (R‐Smad) phosphorylation, TGFβ 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‐1β down‐regulated TGFβRII expression at both the protein and mRNA levels and led to inhibition of the TGFβ1‐induced gene expression and Smad2/3 phosphorylation. Moreover, IL‐1β strongly stimulated the expression of inhibitory Smad7. TGFβRII overexpression abolished the loss of TGFβ1 responsiveness induced by IL‐1β. The decrease in TGFβRII required de novo protein synthesis and involved both the NF‐κB and JNK pathways. Conclusion We demonstrate that IL‐1β impairs TGFβ1 signaling through down‐regulation of TGFβRII, which is mediated by the p65/NF‐κB 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.