Dataset Information

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

ACCESS DATA

Publications

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

Similar Datasets

Project description:BackgroundCCAAT enhancer-binding protein (C/EBP)β regulates gene expression in multiple organ systems and cell types, including astrocytes in the central nervous system (CNS). Inflammatory stimuli, interleukin (IL)-1β, tumor necrosis factor-α, human immunodeficiency virus (HIV)-1 and lipopolysaccharide induce astrocyte C/EBPβ expression. C/EBPβ is detectable in brains of Alzheimer's disease (AD), Parkinson's disease (PD) and HIV-1-associated dementia (HAD) patients, yet little is known about how C/EBPβ contributes to astrocyte gene regulation during neuroinflammation.MethodsThe expression of 92 human inflammation genes was compared between IL-1β-treated primary human astrocytes and astrocytes transfected with C/EBPβ-specific small interfering (si)RNA prior to IL-1β treatment for 12 h. Transcripts altered by>two-fold compared to control were subjected to one-way analysis of variance and Newman-Keuls post-test for multiple comparisons. Expression of two genes, cyclooxygenase-2 (COX-2) and bradykinin receptor B2 (BDKRB2) was further confirmed in additional human astrocyte donors. Astrocytes were treated with mitogen-activated protein kinase-selective inhibitors, then with IL-1β for 12 or 24 h followed by COX-2 and BDKRB2, expression analyses.ResultsIL-1β altered expression of 29 of 92 human inflammation genes by at least two-fold in primary human astrocytes in 12 h. C/EBPβ knockdown affected expression of 17 out of 29 IL-1β-regulated genes by>25%. Two genes relevant to neuroinflammation, COX-2 and BDKRB2, were robustly decreased and increased, respectively, in response to C/EBPβ knockdown, and expression was confirmed in two additional donors. COX-2 and BDKRB2 mRNA remained altered in siRNA-transfected astrocytes at 12, 24 or 72 h. Inhibiting p38 kinase (p38K) activation blocked IL-1β-induced astrocyte COX-2 mRNA and protein expression, but not IL-1β-induced astrocyte BDKRB2 expression. Inhibiting extracellular-regulated kinase (ERK)1/2 activation blocked IL-1β-induced BDKRB2 mRNA expression while increasing COX-2 expression.ConclusionThese data support an essential role for IL-1β in the CNS and identify new C/EBPβ functions in astrocytes. Additionally, this work suggests p38K and ERK1/2 pathways may regulate gene expression in a complementary manner to fine tune the IL-1β-mediated astrocyte inflammatory response. Delineating a role for C/EBPβ and other involved transcription factors in human astrocyte inflammatory response may lead to effective therapies for AD, PD, HAD and other neurological disorders.

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.

Dataset Information

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets