Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-α
Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-α
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DOI：
10.1074/jbc.275.5.3687
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发表时间：
2000-02-04
影响因子：
4.8
通讯作者：
de Crombrugghe, B
中科院分区：
文献类型：
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作者：
Murakami, S;Lefebvre, V;de Crombrugghe, B
炎性细胞因子白细胞介素-1（IL-1）和肿瘤坏死因子-α（TNF-α）强烈抑制软骨细胞外基质蛋白基因的表达。我们最近获得的遗传学证据表明，高迁移率族结构域包含转录因子Sox 9所需的软骨形成和表达的软骨细胞特异性基因，包括II型胶原蛋白（Col 2a 1）的基因。我们在这里表明，IL-1和TNF-α导致软骨细胞中Sox 9 mRNA和/或蛋白质水平的显著和快速下降。NF κ B通路抑制剂吡咯烷二硫代氨基甲酸酯阻断IL-1和TNF-α作用的能力表明转录因子NF κ B在Sox 9下调中的作用。I κ B α的显性阴性突变体阻断IL-1和TNF-α对Sox 9依赖性Col 2 α 1增强子元件的抑制的能力进一步支持了这种作用。此外，NF κ B B亚基p65或p50的强制表达也抑制Sox 9依赖性Col 2a 1增强子。由于Sox 9是软骨形成所必需的，因此软骨细胞中IL-1和TNF-α对Sox 9基因的显著下调足以解释这些细胞因子对软骨细胞表型的抑制。Sox 9的下调可能在抑制炎性关节疾病中软骨表型的表达中起关键作用。
The inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) strongly inhibit the expression of genes for cartilage extracellular matrix proteins. We have recently obtained genetic evidence indicating that the high mobility group domain containing transcription factor Sox9 is required for cartilage formation and for expression of chondrocyte-specific genes including the gene for type II collagen (Col2a1). We show here that IL-1 and TNF-alpha cause a marked and rapid decrease in the levels of Sox9 mRNA and/or protein in chondrocytes. A role for the transcription factor NF kappa B in Sox9 down-regulation was suggested by the ability of pyrrolidine dithiocarbamate, an inhibitor of the NF kappa B pathway, to block the effects of IL-1 and TNF-alpha. This role was further supported by the ability of a dominant-negative mutant of I kappa B alpha to block the IL-1 and TNF-alpha inhibition of Sox9-dependent Col2a1 enhancer elements. Furthermore, forced expression of the NF kappa B subunits p65 or p50 also inhibited Sox9-dependent Col2a1 enhancer. Because Sox9 is essential for chondrogenesis, the marked down-regulation of the Sox9 gene by IL-1 and TNF-alpha in chondrocytes is sufficient to account for the inhibition of the chondrocyte phenotype by these cytokines. The down-regulation of Sox9 may have a crucial role in inhibiting expression of the cartilage phenotype in inflammatory joint diseases.