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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
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International audience. ObjectiveExtracellular 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.MethodsTGFβ1-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.ResultsIL-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.ConclusionWe 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.
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