Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification
[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 promote...
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Veröffentlicht in: | Molecular immunology 2017-03, Vol.83, p.82-91 |
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Sprache: | eng |
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•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. |
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ISSN: | 0161-5890 1872-9142 |
DOI: | 10.1016/j.molimm.2017.01.009 |