Sp1 and Sp3 Transcription Factors Mediate Interleukin-1β Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes
Interleukin-1β (IL-1β) is a pleiotropic cytokine that was shown to inhibit the biosynthesis of articular cartilage components. Here we demonstrate that IL-1β inhibits the production of newly synthesized collagens in proliferating rabbit articular chondrocytes and that this effect is accompanied b...
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Veröffentlicht in: | The Journal of biological chemistry 2003-10, Vol.278 (41), p.39762 |
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Sprache: | eng |
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Zusammenfassung: | Interleukin-1β (IL-1β) is a pleiotropic cytokine that was shown to inhibit the biosynthesis of articular cartilage components.
Here we demonstrate that IL-1β inhibits the production of newly synthesized collagens in proliferating rabbit articular chondrocytes
and that this effect is accompanied by a decrease in the steady-state levels of type II collagen mRNA. IL-1β down-regulates
COL2A1 gene transcription through a â41/â33 bp sequence that binds a multimeric complex including Sp1 and Sp3 transcription factors.
Specificity of IL-1β effects on COL2A1 promoter activity was demonstrated in experiments in which transfection of a wild type â50/+1 sequence of COL2A1 promoter as a decoy oligonucleotide abolished the IL-1β inhibition of a â63/+47 COL2A1- mediated transcription. By contrast, transfection of the related oligonucleotide harboring a targeted mutation in the â41/â33
sequence did not modify the negative effect the cytokine. Because we demonstrated previously that Sp1 was a strong activator
of COL2A1 gene expression via the â63/+1 promoter region, whereas Sp3 overexpression blocked Sp1-induced promoter activity and inhibited
COL2A1 gene transcription, we conclude that IL-1β down-regulation of that gene, as we found previously for transforming growth factor-β1,
is mediated by an increase in the Sp3/Sp1 ratio. Moreover, IL-1β increased steady-state levels of Sp1 and Sp3 mRNAs, whereas
it enhanced Sp3 protein expression and inhibited Sp1 protein biosynthesis. Nevertheless, IL-1β decreased the binding activity
of both Sp1 and Sp3 to the 63-bp short COL2A1 promoter, suggesting that the cytokine exerts a post-transcriptional regulatory mechanism on Sp1 and Sp3 gene expressions.
Altogether, these data indicate that modulation of Sp3/Sp1 ratio in cartilage could be a potential target to prevent or limit
the tissue degradation. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M303541200 |