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Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes.
Arthritis Rheum. 2007 Sep; 56(9):3020-32.AR

Abstract

OBJECTIVE

Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1beta (IL-1beta) and transforming growth factor beta1 (TGFbeta1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1beta on TGFbeta receptor type II (TGFbetaRII) regulation and TGFbeta1 responsiveness in human articular chondrocytes.

METHODS

TGFbeta1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (R-Smad) phosphorylation, TGFbeta 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-1beta down-regulated TGFbetaRII expression at both the protein and mRNA levels and led to inhibition of the TGFbeta1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1beta strongly stimulated the expression of inhibitory Smad7. TGFbetaRII overexpression abolished the loss of TGFbeta1 responsiveness induced by IL-1beta. The decrease in TGFbetaRII required de novo protein synthesis and involved both the NF-kappaB and JNK pathways.

CONCLUSION

We demonstrate that IL-1beta impairs TGFbeta1 signaling through down-regulation of TGFbetaRII, which is mediated by the p65/NF-kappaB 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.

Authors+Show Affiliations

University of Caen Lower Normandy, Caen, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17763417

Citation

Baugé, C, et al. "Interleukin-1beta Impairment of Transforming Growth Factor Beta1 Signaling By Down-regulation of Transforming Growth Factor Beta Receptor Type II and Up-regulation of Smad7 in Human Articular Chondrocytes." Arthritis and Rheumatism, vol. 56, no. 9, 2007, pp. 3020-32.
Baugé C, Legendre F, Leclercq S, et al. Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes. Arthritis Rheum. 2007;56(9):3020-32.
Baugé, C., Legendre, F., Leclercq, S., Elissalde, J. M., Pujol, J. P., Galéra, P., & Boumédiene, K. (2007). Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes. Arthritis and Rheumatism, 56(9), 3020-32.
Baugé C, et al. Interleukin-1beta Impairment of Transforming Growth Factor Beta1 Signaling By Down-regulation of Transforming Growth Factor Beta Receptor Type II and Up-regulation of Smad7 in Human Articular Chondrocytes. Arthritis Rheum. 2007;56(9):3020-32. PubMed PMID: 17763417.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes. AU - Baugé,C, AU - Legendre,F, AU - Leclercq,S, AU - Elissalde,J M, AU - Pujol,J P, AU - Galéra,P, AU - Boumédiene,K, PY - 2007/9/1/pubmed PY - 2007/12/6/medline PY - 2007/9/1/entrez SP - 3020 EP - 32 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 56 IS - 9 N2 - OBJECTIVE: Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1beta (IL-1beta) and transforming growth factor beta1 (TGFbeta1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1beta on TGFbeta receptor type II (TGFbetaRII) regulation and TGFbeta1 responsiveness in human articular chondrocytes. METHODS: TGFbeta1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (R-Smad) phosphorylation, TGFbeta 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-1beta down-regulated TGFbetaRII expression at both the protein and mRNA levels and led to inhibition of the TGFbeta1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1beta strongly stimulated the expression of inhibitory Smad7. TGFbetaRII overexpression abolished the loss of TGFbeta1 responsiveness induced by IL-1beta. The decrease in TGFbetaRII required de novo protein synthesis and involved both the NF-kappaB and JNK pathways. CONCLUSION: We demonstrate that IL-1beta impairs TGFbeta1 signaling through down-regulation of TGFbetaRII, which is mediated by the p65/NF-kappaB 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. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/17763417/Interleukin_1beta_impairment_of_transforming_growth_factor_beta1_signaling_by_down_regulation_of_transforming_growth_factor_beta_receptor_type_II_and_up_regulation_of_Smad7_in_human_articular_chondrocytes_ L2 - https://doi.org/10.1002/art.22840 DB - PRIME DP - Unbound Medicine ER -