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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Lipopolysaccharide Induces Macrophage Migration via Prostaglandin D₂ and Prostaglandin E₂

Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan (T.T., T.M., H.O., M.H.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (K.A., Y.U.); Department of Advanced Medicine and Development, Bio Medical Laboratories, Inc., Saitama, Japan (H.H.); and Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan (M.N.)

Lipopolysaccharide (LPS) produces prostaglandins (PGs) concomitant to eliciting macrophage migration. We evaluated the role of PGs in initiating the migration of macrophages, especially focusing on PGD₂ and PGE₂. In RAW264.7 macrophages, cyclooxygenase (COX)-2 inhibitor, CAY10404 [3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole], completely inhibited LPS-mediated migration at 4 h (early phase) but only partially inhibited the migration at 8 h (late phase), suggesting the presence of PG-dependent and -independent pathways. In the early phase, LPS up-regulated mRNA expressions of COX-2, hematopoietic PGD synthase (H-PGDS), and microsomal-PGE synthase 1, increasing PGD₂ and PGE₂ substantially. The chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTH2) agonist, DK-PGD₂ (13–14-dihydro-15-keto-PGD₂), and the EP4 agonist, ONO-AE1-329 (16-{3-methoxymethyl}phenyl--tetranor-3,7-dithia-prostaglandin E₁), but not selective agonists of D prostanoid receptor, E prostanoid receptor (EP) 2, or EP3, stimulated random migration (chemokinesis). In peritoneal macrophages from CRTH2-deficient and H-PGDS-deficient mice, LPS-mediated migration was significantly inhibited at either early or late phases of the migration. The H-PGDS inhibitor, HQL-79 [4-(diphenylmethoxy)-1-[3-(1H-tetrazol-5-yl)propyl-piperidine]], partially inhibited the migration of the RAW264.7 macrophage in both phases. These results suggest the importance of the PGD₂/CRTH2 pathway in LPS-mediated migration of macrophages. In the late phase of migration, LPS up-regulated monocyte chemoattractant protein (MCP)-1 mRNA. The CC chemokine receptor (CCR2) antagonist, RS102895 [1'-[2-[4-(trifluoromethyl)phenyl]ethyl]-spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one], inhibited LPS-mediated migration in the late phase without affecting the early phase. ONO-AE1-329, but not DK-PGD₂, up-regulated MCP-1 mRNA. Taken together, LPS stimulation of chemokinesis or chemotaxis, or both, occurs in macrophages via PGD₂ and PGE₂ in tandem arrangement; i.e., 1) LPS stimulates prostaglandin signaling, initiating early migration through the PGD₂/CRTH2 and PGE₂/EP4 signaling pathways; and 2) LPS leads induction of MCP-1, which contributes to later phase migration of the macrophages through the PGE₂/EP4 pathway.

Address correspondence to: Dr. Masatoshi Hori, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. E-mail: ahori{at}mail.ecc.u-tokyo.ac.jp

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