title: Synergistic effect of PGD2 via prostanoid DP receptor on TNF-alpha-induced production of MCP-1 and IL-8 in human monocytic THP-1 cells.
abstract: Prostaglandin (PG) D2, a major cyclooxygenase metabolite generated predominantly from immunologically stimulated mast cells, is thought to contribute to the pathogenesis of allergic diseases via the two PGD2 receptors, prostanoid DP receptor and chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). Monocytes are known to express the prostanoid DP receptor, however, the role of it in inflammatory responses is still unclear. In the present study, to clarify the functional roles of prostanoid DP receptor on monocytes, we examined the effect of PGD2 on the production of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 from a human monocytic cell line, THP-1. Single activation of prostanoid DP receptor hardly produced any cytokines or chemokines. However, activation with PGD2 in the presence of tumor necrosis factor (TNF)-alpha mediated significant production of MCP-1 and IL-8, but not the other cytokines and chemokines, in comparison to single stimulation with TNF-alpha. In addition, the selective prostanoid DP receptor antagonist, pinagladin ((Z)-7-[(1R,2R,3S,5S)-2-(benzothiophen-3-ylcarbonylamide)-10-norpinan-3-yl]hept-5-enoic acid) inhibited the production of MCP-1 and IL-8 upon combined stimulation with PGD2 and TNF-alpha. The synergistic production of MCP-1 and IL-8 by PGD2 was mimicked by dibutyryl cAMP (db-cAMP) and was inhibited by a protein kinase A (PKA) inhibitor. Our findings suggest that activation of the prostanoid DP receptor on THP-1 cells enhances TNF-alpha-induced MCP-1 and IL-8 production via the cAMP/PKA signaling pathway.
authors.affiliation: Frontier Drug Discovery, Discovery Research Laboratories, Shionogi and Co., Ltd., 3-1-1, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hirano
authors.forename: Michitaka
authors.initials: M
authors.lastname: Shichijo
authors.forename: Masashi
authors.initials: M
authors.lastname: Deguchi
authors.forename: Morio
authors.initials: M
authors.lastname: Nagira
authors.forename: Noriko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishitani
authors.forename: Maki
authors.initials: M
authors.lastname: Hattori
authors.forename: Akinori
authors.initials: A
authors.lastname: Arimura
mesh_terms: D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D018925:Chemokines / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D009000:Monocytes / Q000378:metabolism; D015230:Prostaglandin D2 / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha
chemical_list: C519549:(Z)-7-((1R,2R,3S,5S)-2-(benzothiophen-3-ylcarbonylamide)-10-norpinan-3-yl)hept-5-enoic acid; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D006538:Heptanoic Acids; D016209:Interleukin-8; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor