c-Jun/activator protein-1 mediates interleukin-1beta-induced dedifferentiation but not cyclooxygenase-2 expression in articular chondrocytes.
Interleukin (IL)-1beta 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-1beta-induced dedifferentiation and cyclooxygenase (COX)-2 expression in primary cultured chondrocytes. IL-1beta 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-1beta-induced dedifferentiation. Interestingly, modulation of c-Jun expression did not affect IL-1beta-induced COX-2 expression. Further experiments revealed that c-Jun phosphorylation was mediated by c-Jun N-terminal kinase and was required for IL-1beta-induced dedifferentiation but not COX-2 expression. Consistent with its ability to induce phosphorylation of c-Jun, IL-1beta caused transient activation of AP-1, which is necessary for IL-1beta-induced dedifferentiation. IL-1beta 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-1beta-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-1beta 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.
Hwang
Sang-Gu
SG
Department of Life Science, Gwangju Institute of Science and Technology, Korea.
Yu
Sung-Sook
SS
Poo
Haryoung
H
Chun
Jang-Soo
JS
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology*; D051546:Cyclooxygenase 2; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006609:High Mobility Group Proteins / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D011817:Rabbits; D055758:SOX9 Transcription Factor; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology
D006609:High Mobility Group Proteins; D007375:Interleukin-1; D016755:Proto-Oncogene Proteins c-jun; D055758:SOX9 Transcription Factor; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014212:Tretinoin; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D048031:JNK Mitogen-Activated Protein Kinases