Differential free fatty acid receptor-1 (FFAR1/GPR40) signalling is associated with gene expression or gelatinase granule release in bovine neutrophils

Innate Immun. 2016 Aug;22(6):479-89. doi: 10.1177/1753425916656765. Epub 2016 Jun 30.


Fatty acids have been recognized as regulators of immune function in addition to their known metabolic role. Long-chain fatty acids bind free fatty acid receptor (FFAR)-1/GPR40, which is expressed on bovine neutrophils, and increase responses such as granule release and gene expression. In this study, we investigated the molecular mechanisms governing the up-regulation of cyclooxygenase-2 (COX-2) and IL-8, as well as matrix metalloproteinase (MMP)-9 granule release in FFAR1/GPR40 agonist-stimulated neutrophils. Our results showed that natural (oleic and linoleic acid) and synthetic (GW9508) FFAR1/GPR40 agonists increased ERK1/2, p38 MAPK and Akt phosphorylation, and that the FFAR1/GPR40 antagonist GW1100 reduced these responses. We evaluated the levels of IκBα, a component of the classical activation pathway of the transcription factor NF-κB, and we observed IκBα reduction after stimulation with FFAR1/GPR40 agonists, an effect that was inhibited by GW1100 or the inhibitors UO126, SB203580 or LY294002. FFAR1/GPR40 agonists increased COX-2 and IL-8 expression, which was inhibited by GW1100 and an NF-κB inhibitor. Finally, the FFAR1/GPR40 agonist-induced MMP-9 granule release was reduced by GW1100 and UO126. In conclusion, FFAR1/GPR40 agonists differentially stimulate neutrophil functions; COX-2 and IL-8 are expressed after FFAR1/GPR40 activation via NF-κB, IκBα reduction is FFAR1/GPR40- and PI3K/MAPK-dependent, and MMP-9 granule release is FFAR1/GPR40- and ERK1/2-dependent.

Keywords: COX-2; FFAR1/GPR40; IL-8; MMP-9; NF-κB; Neutrophils.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / pharmacology
  • Cattle
  • Cell Degranulation
  • Cells, Cultured
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Gelatinases / genetics
  • Gelatinases / metabolism*
  • Gene Expression Regulation
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neutrophils / drug effects
  • Neutrophils / physiology*
  • Pyrimidines / pharmacology
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Secretory Vesicles / metabolism*
  • Signal Transduction* / drug effects


  • Benzoates
  • FFAR1 protein, human
  • GW1100
  • Interleukin-8
  • NF-kappa B
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • Cyclooxygenase 2
  • Gelatinases