title: Differential free fatty acid receptor-1 (FFAR1/GPR40) signalling is associated with gene expression or gelatinase granule release in bovine neutrophils.
abstract: 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.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile Department of Biology, Universidad de Nariño, Pasto, Colombia.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Mena
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile Institute of Pharmacy, Faculty of Sciences, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Manosalva
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Carretta
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Teuber
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Iván
authors.initials: I
authors.lastname: Olmo
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Burgos
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile mahidalgo@uach.cl.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002417:Cattle; D015550:Cell Degranulation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001565:Benzoates; C473034:FFAR1 protein, human; C515631:GW1100; D016209:Interleukin-8; D016328:NF-kappa B; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D051546:Cyclooxygenase 2; D018093:Gelatinases
keywords: COX-2; FFAR1/GPR40; IL-8; MMP-9; NF-κB; Neutrophils