Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK.
Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01-25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10-25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.
['Rutting|Sandra|S|', 'Xenaki|Dia|D|', 'Malouf|Monique|M|', 'Horvat|Jay C|JC|', 'Wood|Lisa G|LG|', 'Hansbro|Philip M|PM|', 'Oliver|Brian G|BG|0000-0002-7122-9262']
D000328:Adult D000368:Aged D002478:Cells, Cultured D005232:Fatty Acids, Volatile D005260:Female D005347:Fibroblasts D006801:Humans D007249:Inflammation D015850:Interleukin-6 D016209:Interleukin-8 D008168:Lung D020935:MAP Kinase Signaling System D008297:Male D059630:Mesenchymal Stem Cells D008875:Middle Aged D032389:Myocytes, Smooth Muscle D011956:Receptors, Cell Surface D043562:Receptors, G-Protein-Coupled D014409:Tumor Necrosis Factor-alpha D048051:p38 Mitogen-Activated Protein Kinases
short-chain fatty acids inflammation human lung mesenchymal cells asthma free fatty acid receptor 3