4.5 Article

Short-chain fatty acids increase TNF alpha-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00306.2018

Keywords

asthma; free fatty acid receptor 3; human lung mesenchymal cells; inflammation; short-chain fatty acids

Funding

  1. National Health and Medical Research Council (NHMRC) of Australia
  2. Faculty of Health and Medicine
  3. Rainbow Foundation
  4. NHMRC of Australia [APP1110368]

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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)alpha-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 TNF alpha, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNF alpha-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 TNF alpha resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNF alpha alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNF alpha-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.

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