Frontier Research Laboratories, R&D Division, Daiichi Sankyo Company, Limited, Tokyo 140-871, Japan.
J Biol Chem. 2013 Apr 12;288(15):10684-91. doi: 10.1074/jbc.M112.420042. Epub 2013 Feb 28.
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.
G 蛋白偶联受体 84（GPR84）是一种假定的中链脂肪酸（MCFA）受体，其病理生理作用尚未阐明。在这里，我们表明，GPR84 被带有 2 位或 3 位羟基的 MCFAs 比非羟基 MCFAs 更有效地激活。我们还鉴定了 GPR84 的替代激动剂 6-正辛基氨基尿嘧啶（6-OAU）。这些潜在的配体和替代激动剂 6-OAU 以 GPR84 依赖的方式刺激 [(35)S]GTP 结合和积累磷酯酰肌醇。替代激动剂 6-OAU 将 GPR84-EGFP 从细胞表面内化。潜在的配体和 6-OAU 都能趋化人多形核白细胞（PMN）和巨噬细胞，并放大 LPS 刺激的 PMN 产生促炎细胞因子 IL-8 和巨噬细胞产生 TNFα。此外，6-OAU 的静脉注射可提高大鼠血液中 CXCL1 的水平，6-OAU 接种到大鼠气囊中可使PMN 和巨噬细胞在该部位聚集。我们的研究结果表明 GPR84 具有促炎作用，这表明该受体可能是治疗与慢性低度炎症相关疾病的新靶点。
