Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification

• Published in: Molecular immunology Vol. 83; pp. 82 - 91
• Main 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2017
• Subjects: acetylation; acetyltransferases; Adalimumab - pharmacology; adverse effects; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Blotting, Western; CCL2; chemokine CCL2; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; chromatin; Chromatin Immunoprecipitation; DNA Methylation; enzyme-linked immunosorbent assay; Epigenesis, Genetic; Epigenetic regulation; epigenetics; Etanercept - pharmacology; gene expression; gene expression regulation; Gene Expression Regulation - drug effects; histones; Histones - genetics; Histones - metabolism; Humans; immunomodulation; methyltransferases; mitogen-activated protein kinase; Monocyte; monocytes; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; pathogenesis; precipitin tests; promoter regions; Promoter Regions, Genetic - genetics; Rheumatoid arthritis; TNF-α inhibitors; transcription factor NF-kappa B; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Western blotting; MCP-1; pp65; Epigenetic regulation; ChIP; LPS; H3K36me3; Cmin; CBP; pp38; NF-κB; CCL2; Cmax; IL; pJNK; Monocyte; H3K4me3; H3K79me3; H3; MAPK; RA; TNF-α; Rheumatoid arthritis; HAT; SEM; pERK; PCAF; HDAC; ELISA; H3K27me3; TNF-α inhibitors
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2017.01.009

[Display omitted] •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. 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.