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

Abstract

Objective. Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1␤ (IL-1␤) and transforming growth factor ␤1 (TGF␤1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1␤ on TGF␤ receptor type II (TGF␤RII) regulation and TGF␤1 responsiveness in human articular chondrocytes.Methods. TGF␤1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (RSmad) phosphorylation, TGF␤ 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-1␤ down-regulated TGF␤RII expression at both the protein and mRNA levels and led to inhibition of the TGF␤1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1␤ strongly stimulated the expression of inhibitory Smad7.TGF␤RII overexpression abolished the loss of TGF␤1 responsiveness induced by IL-1␤. The decrease in TGF␤RII required de novo protein synthesis and involved both the NF-B and JNK pathways.Conclusion. We demonstrate that IL-1␤ impairs TGF␤1 signaling through down-regulation of TGF␤RII, which is mediated by the p65/NF-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.

Interleukin 2-mediated Conversion of Ovarian Cancer-associated CD4+ Regulatory T Cells Into Proinflammatory Interleukin 17-producing Helper T Cells

“…21 In addition, in both murine models and in humans, IL-2 has been described as indispensable for the differentiation of T reg , but deleterious to the differentiation of T H 17 cells. 34 37 In line with this hypothesis, using a murine model of FOXP3 knock-in mice, Xu et al 38 have recently proposed that, in addition to their ability to induce T H 17 cells from conventional CD4 + T cells, T reg can also be self-induced to become T H 17 cells in the absence of exogenous TGF-b.…”

Influence of the Molecular Weight of Poly(Lactide-Co-Glycolide) on theIn VivoCartilage Repair by a Construct of Poly(Lactide-Co-Glycolide)/Fibrin Gel/Mesenchymal Stem Cells/Transforming Growth Factor-β1

“…The IL-1b and TNFa in the injured cartilage positively regulate the activity of NF-jB, which is able to block the expression of SOX9. 41 In addition, NF-jB can downregulate the expression of TGF-b receptor type II, 42 impairing the TGF-b1 signaling and finally interfering with the chondrogenesis of MSCs. Potent inhibition of the master chondrogenic factor SOX9 gene by IL-1b and TNFa was also observed by other researchers previously.…”

CCN1 contributes to skin connective tissue aging by inducing age-associated secretory phenotype in human skin dermal fibroblasts

“…Interestingly, IL-1β has been shown to impair TGF-β signaling by down-regulation of TGF-β type II receptor, thereby promoting development of degenerative and inflammatory diseases in osteoarthritis (Bauge et al 2007). Therefore, it is possible that elevated CCN1 impairs TGF-β signaling through upregulation of IL-1β, and thereby contributes to aberrant collagen homeostasis in aged human skin dermal fibroblasts.…”