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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:ObjectiveC/EBPβ, a crucial transcription factor, regulates innate immunity and inflammatory responses. However, the role played by C/EBPβ in alveolar macrophage (AM) inflammatory responses remains unknown. This study aimed to investigate the role and mechanism of C/EBPβ in alveolar macrophages (AMs) from the transcriptional level and to search for natural compounds targeting C/EBPβ.MethodsRat AMs were infected with Lv-sh-C/EBPβ and treated with LPS, and the expression levels of iNOS, TNF-α, IL-6, and IL-1β were measured by RT-qPCR, Western blotting, and ELISA. Mechanistically, transcriptome sequencing (RNA-seq) revealed changes in gene expression patterns in AMs after LPS stimulation and C/EBPβ knockdown. Functional enrichment analyses and rescue experiments identified and validated inflammation-associated cell signaling pathways regulated by C/EBPβ. Furthermore, virtual screening was used to search for natural compounds that inhibit C/EBPβ with the structure of helenalin as a reference.ResultsFollowing stimulation with LPS, AMs exhibited an increased expression of C/EBPβ. C/EBPβ knockdown significantly decreased the expression levels of inflammatory mediators. A total of 374 differentially expressed genes (DEGs) were identified between LPS-stimulated C/EBPβ knockdown and negative control cells. The NOD-like receptor signaling may be a key target for C/EBPβ, according to functional enrichment analyses of the DEGs. Further experiments showed that the muramyl dipeptide (MDP, NOD2 agonist) reversed the downregulation of inflammatory mediators and the NF-κB pathway caused by the C/EBPβ knockdown. The virtual screening revealed that N-caffeoyltryptophan, orilotimod, and petasiphenone have comparable pharmacological properties to helenalin (a known C/EBPβ inhibitor) and demonstrate a great binding capacity to C/EBPβ.ConclusionAblation of C/EBPβ may attenuate LPS-induced inflammatory damage in AMs by inhibiting the NOD2 receptor signaling pathway. Three natural compounds, N-caffeoyltryptophan, orilotimod, and petasiphenone, may be potential C/EBPβ inhibitors.

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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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