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Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with toll-like receptor ligands.

ABSTRACT: Short-chain fatty acids (SCFAs), produced at relatively high levels by anaerobic bacteria in bacterial vaginosis (BV), are believed to be anti-inflammatory. BV, a common alteration in the genital microbiota associated with increased susceptibility to HIV infection, is characterized by increased levels of both pro-inflammatory cytokines and SCFAs. We investigated how SCFAs alone or together with Toll-like receptor (TLR) ligands affected pro-inflammatory cytokine secretion.Cytokines were measured by ELISA. Flow was used for phenotyping and reactive oxygen species (ROS) measurement.Short-chain fatty acids, at 20 mM, induced interleukin (IL)-8, IL-6, and IL-1? release, while lower levels (0.02-2 mM) did not induce cytokine secretion. Levels >20 mM were toxic to cells. Interestingly, lower levels of SCFAs significantly enhanced TLR2 ligand- and TLR7 ligand-induced production of IL-8 and TNF? in a time- and dose-dependent manner, but had little effect on lipopolysaccharide-induced cytokine release. SCFAs mediated their effects on pro-inflammatory cytokine production at least in part by inducing the generation of ROS.Our data suggest that SCFAs, especially when combined with specific TLR ligands, contribute to a pro-inflammatory milieu in the lower genital tract and help further our understanding of how BV affects susceptibility to microbial infections.

SUBMITTER: Mirmonsef P

PROVIDER: S-EPMC3288536 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with toll-like receptor ligands.

Mirmonsef Paria P Zariffard Mohammad R MR Gilbert Douglas D Makinde Hadijat H Landay Alan L AL Spear Greg T GT

American journal of reproductive immunology (New York, N.Y. : 1989) 20111108 5

<h4>Problem</h4>Short-chain fatty acids (SCFAs), produced at relatively high levels by anaerobic bacteria in bacterial vaginosis (BV), are believed to be anti-inflammatory. BV, a common alteration in the genital microbiota associated with increased susceptibility to HIV infection, is characterized by increased levels of both pro-inflammatory cytokines and SCFAs. We investigated how SCFAs alone or together with Toll-like receptor (TLR) ligands affected pro-inflammatory cytokine secretion.<h4>Meth ...[more]

PMID: 22059850

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Project description:BackgroundChronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs.ObjectiveThe objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43.MethodsWe performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA.ResultsImmunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43.Conclusions and clinical relevanceShort-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

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Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with toll-like receptor ligands.

Publications

Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with toll-like receptor ligands.

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