c-Jun/activator protein-1 mediates interleukin-1β-induced dedifferentiation but not cyclooxygenase-2 expression in articular chondrocytes
c-Jun/activator protein-1 mediates interleukin-1β-induced dedifferentiation but not cyclooxygenase-2 expression in articular chondrocytes
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DOI：
10.1074/jbc.m411793200
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发表时间：
2005-08-19
影响因子：
4.8
通讯作者：
Chun, JS
中科院分区：
文献类型：
--
作者：
Hwang, SG;Yu, SS;Chun, JS
白介素1β是一种主要的分解代谢促炎细胞因子，参与软骨破坏相关的过程，如软骨细胞表型丧失(去分化)和炎症。在此，我们研究了c-jun和激活蛋白-1(AP-1)在IL-1β诱导原代培养软骨细胞去分化和环氧合酶-2表达中的作用。IL-1β诱导原代培养软骨细胞c-jun表达及瞬时磷酸化。C-jun的异位表达足以引起去分化，而显性阴性c-jun的表达可阻断IL-1β诱导的去分化。有趣的是，c-jun表达的调节并不影响IL-1β诱导的COX-2的表达。进一步的实验表明，c-jun的磷酸化是由c-jun氨基末端激酶介导的，并且是IL-1β诱导的去分化所必需的，而不是COX-2的表达。与其诱导c-jun磷酸化的能力一致，IL-1β导致AP-1的瞬时激活，而AP-1是IL-1β诱导去分化所必需的。IL-1β治疗抑制了SOX-9的表达，SOX-9是调节II型胶原表达的主要转录因子。抑制c-Jun氨基末端激酶或AP-1可逆转IL-1β诱导的SOX-9抑制，c-Jun的异位表达足以引起SOX-9的抑制。我们的结果表明，IL-1β通过诱导c-jun的表达和磷酸化、AP-1的激活以及随后抑制SOX-9来抑制关节软骨细胞中II型胶原的表达。
Interleukin (IL)-1 beta is a major catabolic pro-inflammatory cytokine involved in cartilage destruction-associated processes, such as loss of the differentiated chondrocyte phenotype ( dedifferentiation) and inflammation. Here, we investigated the role of c-Jun and activator protein-1 (AP-1) in IL-1 beta-induced dedifferentiation and cyclooxygenase ( COX)-2 expression in primary cultured chondrocytes. IL-1 beta induced expression and transient phosphorylation of c-Jun in primary cultured chondrocytes. Ectopic expression of c-Jun was sufficient to cause dedifferentiation, whereas expression of dominant negative c-Jun blocked IL-1 beta-induced dedifferentiation. Interestingly, modulation of c-Jun expression did not affect IL-1 beta-induced COX-2 expression. Further experiments revealed that c-Jun phosphorylation was mediated by c-Jun N-terminal kinase and was required for IL-1 beta-induced dedifferentiation but not COX-2 expression. Consistent with its ability to induce phosphorylation of c-Jun, IL-1 beta caused transient activation of AP-1, which is necessary for IL-1 beta-induced dedifferentiation. IL-1 beta treatment suppressed expression of Sox-9, a major transcription factor that regulates type II collagen expression. Inhibition of c-Jun N-terminal kinase or AP-1 reversed IL-1 beta-induced suppression of Sox- 9, and ectopic expression of c-Jun was sufficient to cause suppression of Sox-9. Our results collectively suggest that IL-1 beta suppresses type II collagen expression in articular chondrocytes by inducing expression and phosphorylation of c-Jun, AP-1 activation, and subsequent suppression of Sox-9.