Abstract
Short-chain fatty acid (SCFA) acetate, a byproduct of dietary fiber metabolism by gut bacteria, has multiple immunomodulatory functions. The anti-inflammatory role of acetate is well documented; however, its effect on monocyte chemoattractant protein-1 (MCP-1) production is unknown. Similarly, the comparative effect of SCFA on MCP-1 expression in monocytes and macrophages remains unclear. We investigated whether acetate modulates TNFα-mediated MCP-1/CCL2 production in monocytes/macrophages and, if so, by which mechanism(s). Monocytic cells were exposed to acetate with/without TNFα for 24 h, and MCP-1 expression was measured. Monocytes treated with acetate in combination with TNFα resulted in significantly greater MCP-1 production compared to TNFα treatment alone, indicating a synergistic effect. On the contrary, treatment with acetate in combination with TNFα suppressed MCP-1 production in macrophages. The synergistic upregulation of MCP-1 was mediated through the activation of long-chain fatty acyl-CoA synthetase 1 (ACSL1). However, the inhibition of other bioactive lipid enzymes [carnitine palmitoyltransferase I (CPT I) or serine palmitoyltransferase (SPT)] did not affect this synergy. Moreover, MCP-1 expression was significantly reduced by the inhibition of p38 MAPK, ERK1/2, and NF-κB signaling. The inhibition of ACSL1 attenuated the acetate/TNFα-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB. Increased NF-κB/AP-1 activity, resulting from acetate/TNFα co-stimulation, was decreased by ACSL1 inhibition. In conclusion, this study demonstrates the proinflammatory effects of acetate on TNF-α-mediated MCP-1 production via the ACSL1/MAPK/NF-κB axis in monocytic cells, while a paradoxical effect was observed in THP-1-derived macrophages.
Original language | English |
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Journal | International Journal of Molecular Sciences |
Volume | 22 |
Issue number | 14 |
DOIs | |
Publication status | Published - 19 Jul 2021 |
Keywords
- Acetates/administration & dosage
- Chemokine CCL2/biosynthesis
- Coenzyme A Ligases/antagonists & inhibitors
- Drug Synergism
- Enzyme Inhibitors/pharmacology
- Fatty Acids, Volatile/administration & dosage
- Humans
- MAP Kinase Signaling System
- Models, Biological
- Monocytes/drug effects
- NF-kappa B/metabolism
- Obesity/etiology
- Phosphorylation
- RNA, Messenger/genetics
- THP-1 Cells
- Triazenes/pharmacology
- Tumor Necrosis Factor-alpha/administration & dosage