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SOCS1 suppresses IL-1?-induced C/EBP? expression via transcriptional regulation in human chondrocytes.

ABSTRACT: CAAT/enhancer-binding protein-beta (C/EBP?) is a transcription factor that regulates interleukin-1? (IL-1?)-induced catabolic pathways, including the expression of matrix metalloproteinases (MMPs), in chondrocytes. We previously reported that suppressor of cytokine signaling 1 (SOCS1) inhibits IL-1? signaling in chondrocytes. However, the effect of SOCS1 on C/EBP? has not been explored. To investigate the interaction between SOCS1 and C/EBP?, we established human SW1353 cells with overexpression or knockdown of SOCS1 or C/EBP?. Both SOCS1 and C/EBP? were involved in transcription of MMP-3 and MMP-13. When stimulated with IL-1?, C/EBP? levels were significantly increased by SOCS1 knockdown and decreased by SOCS1 overexpression. A similar change in IL-1?-induced C/EBP? expression was observed in SOCS1-transfected human articular chondrocytes. However, C/EBP? overexpression or knockdown did not change the levels of IL-1?-induced SOCS1. SOCS1 regulated the levels of C/EBP? mRNA by ubiquitination of C/EBP? as well as transcriptional regulation. Furthermore, it suppressed the phosphorylation of cAMP response element-binding protein (CREB), an active transcription factor of C/EBP?. In addition, p38 mitogen-activated protein kinases, a target of SOCS1, was involved in CREB phosphorylation. The chromatin immunoprecipitation assay confirmed that SOCS1 overexpression led to reduced binding of C/EBP? to the MMP-13 promoter. Taken together, our results demonstrate that SOCS1 downregulates the p38-CREB-C/EBP? pathway resulting in increased expression of MMPs in chondrocytes.

SUBMITTER: Ha YJ

PROVIDER: S-EPMC4929694 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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SOCS1 suppresses IL-1β-induced C/EBPβ expression via transcriptional regulation in human chondrocytes.

Ha You-Jung YJ Choi Yong Seok YS Kang Eun Ha EH Shin Kichul K Kim Tae Kyun TK Song Yeong Wook YW Lee Yun Jong YJ

Experimental & molecular medicine 20160624

CAAT/enhancer-binding protein-beta (C/EBPβ) is a transcription factor that regulates interleukin-1β (IL-1β)-induced catabolic pathways, including the expression of matrix metalloproteinases (MMPs), in chondrocytes. We previously reported that suppressor of cytokine signaling 1 (SOCS1) inhibits IL-1β signaling in chondrocytes. However, the effect of SOCS1 on C/EBPβ has not been explored. To investigate the interaction between SOCS1 and C/EBPβ, we established human SW1353 cells with overexpression ...[more]

PMID: 27339399

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Project description:There is growing evidence in support of the involvement of inflammatory response in the pathogenesis of osteoarthritis (OA). Harpagoside, one of the bioactive components of Harpagophytum procumbens (Hp), has been shown to possess anti-inflammatory properties. Here we used an in vitro model of inflammation in OA to investigate the potential of harpagoside to suppress the production of inflammatory cytokines/chemokines such as IL-6 and matrix degrading proteases. We further investigated the likely targets of harpagoside in primary human OA chondrocytes. OA chondrocytes were pre-treated with harpagoside before stimulation with IL-1?. mRNA expression profile of 92 cytokines/chemokines was determined using TaqMan Human Chemokine PCR Array. Expression levels of selected mRNAs were confirmed using TaqMan assays. Protein levels of IL-6 and MMP-13 were assayed by ELISA and immunoblotting. Total protein levels and phosphorylation of signaling proteins were determined by immunoblotting. Cellular localization of IL-6 and c-Fos was performed by immunofluorescence and confocal microscopy. DNA binding activity of c-FOS/AP-1 was determined by ELISA. Harpagoside significantly altered the global chemokine expression profile in IL-1?-stimulated OA chondrocytes. Expression of IL-6 was highly induced by IL-1?, which was significantly inhibited by pre-treatment of OA chondrocytes with harpagoside. Harpagoside did not inhibit the IL-1?-induced activation of NF-?B and C/EBP? transcription factors but suppressed the IL-1?-triggered induction, phosphorylation, and DNA binding activity of c-FOS, one of the main components of AP-1 transcription factors. Further, harpagoside significantly inhibited the expression of MMP-13 in OA chondrocytes under pathological conditions. siRNA-mediated knockdown of IL-6 resulted in suppressed expression and secretion of MMP-13 directly linking the role of IL-6 with MMP-13 expression. Taken together, the present study suggests that harpagoside exerts a significant anti-inflammatory effect by inhibiting the inflammatory stimuli mediated by suppressing c-FOS/AP-1 activity in OA chondrocytes under pathological conditions. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:311-320, 2017.

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SOCS1 suppresses IL-1?-induced C/EBP? expression via transcriptional regulation in human chondrocytes.

Publications

SOCS1 suppresses IL-1β-induced C/EBPβ expression via transcriptional regulation in human chondrocytes.

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