NF-kappaB Inhibits Expression of the alpha1(I) Collagen Gene

Rippe, Richard A.; Schrum, Laura W.; Stefanovic, Branko; Solı́s-Herruzo, José A.; Brenner, David A.

doi:10.1089/104454999314890

Cited by 143 publications

(112 citation statements)

References 43 publications

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“…In addition, despite the fact that NF-B is commonly described as an activator transcription factor, our results strongly support its involvement in the inhibition of TGF␤RII expression. That NF-B could downregulate transcription is also consistent with studies reporting its inhibitory action through direct interaction with DNA at Sp-1-like sites (32) or by sequestration of CBP/p300 transcription coactivators (33,34). Therefore, we cannot exclude a similar mechanism in the IL-1␤ regulation of TGF␤RII.…”

Section: Discussionsupporting

confidence: 81%

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

Baugé

Legendre

Leclercq

et al. 2007

Arthritis & Rheumatism

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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.

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Section: Discussionsupporting

confidence: 81%

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

Baugé

Legendre

Leclercq

et al. 2007

Arthritis & Rheumatism

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“…We found that the major predentin structural component, type I collagen, was down-regulated by LTA. This finding is in agreement with the fact that NF-B pathway activation decreases expression of ␣1(I) and ␣2(I) collagen genes (44,45). It also indicates that our model of odontoblast stimulation by LTA is relevant to the in vivo situation of active carious lesions.…”

Section: Figuresupporting

confidence: 90%

Lipoteichoic Acid Increases TLR and Functional Chemokine Expression while Reducing Dentin Formation in In Vitro Differentiated Human Odontoblasts

Durand

Flacher

Roméas

et al. 2006

The Journal of Immunology

159

172

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Gram-positive bacteria entering the dentinal tissue during the carious process are suspected to influence the immune response in human dental pulp. Odontoblasts situated at the pulp/dentin interface are the first cells encountered by these bacteria and therefore could play a crucial role in this response. In the present study, we found that in vitro-differentiated odontoblasts constitutively expressed the pattern recognition receptor TLR1–6 and 9 genes but not TLR7, 8, and 10. Furthermore, lipoteichoic acid (LTA), a wall component of Gram-positive bacteria, triggered the activation of the odontoblasts. LTA up-regulated the expression of its own receptor TLR2, as well as the production of several chemokines. In particular, an increased amount of CCL2 and CXCL10 was detected in supernatants from LTA-stimulated odontoblasts, and those supernatants augmented the migration of immature dendritic cells in vitro compared with controls. Clinical relevance of these observations came from immunohistochemical analysis showing that CCL2 was expressed in vivo by odontoblasts and blood vessels present under active carious lesions but not in healthy dental pulps. In contrast with this inflammatory response, gene expression of major dentin matrix components (type I collagen, dentin sialophosphoprotein) and TGF-β1 was sharply down-regulated in odontoblasts by LTA. Taken together, these data suggest that odontoblasts activated through TLR2 by Gram-positive bacteria LTA are able to initiate an innate immune response by secreting chemokines that recruit immature dendritic cells while down-regulating their specialized functions of dentin matrix synthesis and mineralization.

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“…4B). These results suggest that even though IL-1␤ induces NF-B binding activity, the effect of this cytokine on COL2A1 gene expression is not mediated through an increase of p65 binding to a Sp1-responsive element found in COL2A1 promoter, as demonstrated for COL1A1 gene expression (32).…”

Section: A Short Col2a1 63-base Pair Proximal Promoter Mediates Il-1␤mentioning

confidence: 63%

Sp1 and Sp3 Transcription Factors Mediate Interleukin-1β Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes

Chadjichristos¹,

Ghayor²,

Kypriotou³

et al. 2003

Journal of Biological Chemistry

119

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Interleukin-1␤ (IL-1␤) is a pleiotropic cytokine that was shown to inhibit the biosynthesis of articular cartilage components. Here we demonstrate that IL-1␤ 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-1␤ down-regulates COL2A1 gene transcription through a ؊41/؊33 bp sequence that binds a multimeric complex including Sp1 and Sp3 transcription factors. Specificity of IL-1␤ effects on COL2A1 promoter activity was demonstrated in experiments in which transfection of a wild type ؊50/؉1 sequence of COL2A1 promoter as a decoy oligonucleotide abolished the IL-1␤ inhibition of a ؊63/؉47 COL2A1-mediated transcription. By contrast, transfection of the related oligonucleotide harboring a targeted mutation in the ؊41/؊33 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 ؊63/؉1 promoter region, whereas Sp3 overexpression blocked Sp1-induced promoter activity and inhibited COL2A1 gene transcription, we conclude that IL-1␤ down-regulation of that gene, as we found previously for transforming growth factor-␤1, is mediated by an increase in the Sp3/Sp1 ratio. Moreover, IL-1␤ increased steady-state levels of Sp1 and Sp3 mRNAs, whereas it enhanced Sp3 protein expression and inhibited Sp1 protein biosynthesis. Nevertheless, IL-1␤ 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.Articular cartilage is a highly specialized tissue composed of a complex extracellular matrix of proteoglycans, collagens, and noncollagenous glycoproteins. Cartilage collagens include type II as the major form and types VI, IX, and XI as minor components (1). Type II collagen is an homotrimer composed of ␣1(II) chains encoded by the COL2A1 gene. Previous studies have delineated minimal sequences in the first intron of human, mouse, and rat COL2A1 genes which are sufficient to direct chondrocyte-specific expression in cultured chondrocytes and transgenic mice (2-5). Several binding sites of the intronic enhancer sequences were shown to interact with transcription factors that form chondrocyte-specific complexes, such as SOX9, L-SOX5, and SOX6 (6, 7), and also with factors having less tissue-specific expression, such as Sp1, Sp3, and C-KROX (5, 8). Indeed, promoter sequences are also implicated through interaction with the intronic enhancer sequence, for tissuespecific expression during in vivo and in vitro chondrogenesis (7, 9, 10). In a 266-bp promoter of the human COL2A1 gene mediating enhanced transcription activity, we identified several binding sites for Sp1, Sp3, and C-KROX (5, 8, 11). Sp1 w...

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NF-kappaB Inhibits Expression of the alpha1(I) Collagen Gene

Cited by 143 publications

References 43 publications

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

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

Lipoteichoic Acid Increases TLR and Functional Chemokine Expression while Reducing Dentin Formation in In Vitro Differentiated Human Odontoblasts

Sp1 and Sp3 Transcription Factors Mediate Interleukin-1β Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes

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