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.
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.


CONCLUSIONS
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.
Baugé
C
C
University of Caen Lower Normandy, Caen, France.
Legendre
F
F
Leclercq
S
S
Elissalde
J M
JM
Pujol
J P
JP
Galéra
P
P
Boumédiene
K
K
D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D019902:Chondrocytes / Q000502:physiology*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D007596:Joints / Q000166:cytology*; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction; D051906:Smad7 Protein / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D015854:Up-Regulation
D053583:Interleukin-1beta; D018125:Receptors, Transforming Growth Factor beta; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II