title: Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor.
abstract: G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84. These potential ligands and the surrogate agonist, 6-OAU, stimulated [(35)S]GTP binding and accumulated phosphoinositides in a GPR84-dependent manner. The surrogate agonist, 6-OAU, internalized GPR84-EGFP from the cell surface. Both the potential ligands and 6-OAU elicited chemotaxis of human polymorphonuclear leukocytes (PMNs) and macrophages and amplified LPS-stimulated production of the proinflammatory cytokine IL-8 from PMNs and TNFα from macrophages. Furthermore, the intravenous injection of 6-OAU raised the blood CXCL1 level in rats, and the inoculation of 6-OAU into the rat air pouch accumulated PMNs and macrophages in the site. Our results indicate a proinflammatory role of GPR84, suggesting that the receptor may be a novel target to treat chronic low grade inflammation associated-disease.
authors: Frontier Research Laboratories, R&D Division, Daiichi Sankyo Company, Limited, Tokyo 140-871, Japan.
authors: Masakatsu
authors: M
authors: Suzuki
authors: Sachiko
authors: S
authors: Takaishi
authors: Miyuki
authors: M
authors: Nagasaki
authors: Yoshiko
authors: Y
authors: Onozawa
authors: Ikue
authors: I
authors: Iino
authors: Hiroaki
authors: H
authors: Maeda
authors: Tomoaki
authors: T
authors: Komai
authors: Tomiichiro
authors: T
authors: Oda
mesh_terms: D000818:Animals; D016466:CHO Cells; D002417:Cattle; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D005227:Fatty Acids; C431700:GPR84 protein, human; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D014498:Uracil