Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification. (March 2017)

• Record Type: Journal Article
• Authors: Lin, Yi-Ching; Lin, Yu-Chih; Huang, Ming-Yii; Kuo, Po-Lin; Wu, Cheng-Chin; Lee, Min-Sheng; Hsieh, Chong-Chao; Kuo, Hsuan-Fu; Kuo, Chang-Hung; Tsai, Wen-Chan; Hung, Chih-Hsing
• Is Part Of: Molecular immunology. Volume 83(2017:Mar.)
• Page Start: 82
• Page End: 91
• Publication Date: 2017-03
• Subjects: RA rheumatoid arthritis -- TNF-α tumor necrosis factor-alpha -- MCP-1 chemoattractant protein-1, also called CCL2 -- HAT histone acetyltransferase -- HDAC histone deacetylase -- IL interleukin -- LPS lipopolysaccharide -- ELISA Enzyme-linked immunosorbent assay -- MAPK mitogen-activated protein kinase -- pp38 phospho-p38 -- pERK phospho-ERK -- pJNK phospho-JNK -- pp65 phospho-p65 -- ChIP chromatin immunoprecipitation -- H3 histone 3 -- H3K4me3 trimethylated H3K4 -- H3K27me3 trimethylated H3K27 -- H3K36me3 trimethylated H3K36 -- H3K79me3 H3K79 trimethylation -- CBP CREB-binding protein -- PCAF p300/CBP-associated factor -- NF-κB nuclear factor-κB -- Cmax the maximum serum concentration -- Cmin the minimum serum concentration -- SEM standard error of mean; TNF-α inhibitors -- CCL2 -- Epigenetic regulation -- Rheumatoid arthritis -- Monocyte; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2017.01.009
• Languages: English
• ISSNs: 0161-5890

Abstract

Graphical abstract: Highlights: TNF-α inhibitors suppress CCL2 production in human monocytes. TNF-α inhibitors suppress CCL2 through MAPK and p65-NFκB pathways. TNF-α inhibitors downregulate the histone acetylation in the CCL2 promoter. TNF-α inhibitors downregulate the histone trimethylation in the CCL2 promoter. Abstract: The treatment of rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-α) inhibitors could lead to adverse effects. Therefore, the identification of downstream therapeutic targets is important. Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is related to RA disease activity, and epigenetic modifications are hypothesized to regulate gene expression in RA pathogenesis. We studied the effects of two TNF-α inhibitors, etanercept and adalimumab, on CCL2 expression and the potentially associated intracellular mechanisms, including epigenetic regulation. Etanercept and adalimumab decreased CCL2 production in THP-1 cells and human primary monocytes, as detected using enzyme-linked immunosorbent assays, and these changes in the CCL2 levels were independent of the TNF-α levels. Etanercept and adalimumab suppressed mitogen-activated protein kinase (MAPK) phospho-p38, phospho-JNK, phospho-ERK and nuclear factor-κB (NF-κB) phospho-p65, as demonstrated using western blot analyses. The investigation of epigenetic modifications using chromatin immunoprecipitation revealed that etanercept and adalimumab down-regulated acetylation of histone (H)3 and H4 in the CCL2 promoter region by decreasing the recruitment of the NF-κB associated acetyltransferases p300, CBP and PCAF. Etanercept and adalimumab also down-regulated trimethylation of H3K4, H3K27, H3K36 and H3K79 in the CCL2 promoter region by decreasing the expression of the related methyltransferases WDR5 and Smyd2. We demonstrated that TNF-α inhibitors exert immunomodulatory effects on CCL2 expression in human monocytes via MAPKs, NF-κB and epigenetic modifications. These findings broaden the mechanistic knowledge related to TNF-α inhibitors and provide novel therapeutic targets for RA.