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* Research Unit for Clinical Immunology, RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan;
Department of Medicine and Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan;
Department of Microbiology, Kitasato University School of Allied Health Sciences, Kanagawa, Japan; and
Department of General Medicine, Kitasato University School of Medicine, Kanagawa, Japan
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface molecule that is expressed by neutrophils and monocytes. TREM-1 expression is modulated by various ligands for TLRs in vitro and in vivo. However, the influence of PGE2, a potential mediator of inflammation, on TREM-1 expression has not been elucidated. In this study, we examined the effects of PGE2 on LPS-induced TREM-1 expression by resident murine peritoneal macrophages (RPM) and human PBMC. PGE2 significantly induced murine TREM-1 (mTREM-1) expression by RPM. Up-regulation of TREM-1 expression was specific to PGE2 among arachidonic acid metabolites, while ligands for chemoattractant receptor-homologous molecule expressed on Th2 cells and the thomboxane-like prostanoid receptor failed to induce mTREM-1 expression. PGE2 also increased expression of the soluble form of TREM-1 by PBMC. LPS-induced TREM-1 expression was regulated by endogenous PGE2 especially in late phase (>2 h after stimulation), because cyclooxygenase-1 and -2 inhibitors abolished this effect at that points. A synthetic EP4 agonist and 8-Br-cAMP also enhanced mTREM-1 expression by RPM. Furthermore, protein kinase A, PI3K, and p38 MAPK inhibitors prevented PGE2-induced mTREM-1 expression by RPM. Activation of TREM-1 expressed on PGE2-pretreated PBMC by an agonistic TREM-1 mAb significantly enhanced the production of IL-8 and TNF-
. These findings indicate that LPS-induced TREM-1 expression on macrophages is mediated, at least partly, by endogenous PGE2 followed by EP4 and cAMP, protein kinase A, p38 MAPK, and PI3K-mediated signaling. Regulation of TREM-1 and the soluble form of TREM-1 expression by PGE2 may modulate the inflammatory response to microbial pathogens.
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1 This work was supported in part by a research program of the Graduate School of Medical Sciences, Kitasato University, research grants from the Ministry of Education, Science, Sports and Culture of Japan, and research grants from the Ministry of Health, Labour and Welfare of Japan.
2 Address correspondence and reprint requests to Dr. Yousuke Murakami, Clinical Immunology Unit, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan. E-mail address: y-mura{at}rcai.riken.jp
3 Abbreviations used in this paper: TREM, triggering receptor expressed on myeloid cells; mTREM, murine TREM; hTREM, human TREM; sTREM, soluble form of TREM; hsTREM, human sTREM; PKA, protein kinase A; COX, cyclooxygenase; RPM, resident peritoneal macrophage; I-BOP, 1S-[1, 2(Z),3
(1E,3S),4]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; TP, thromboxane-like prostanoid; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; EP, E-series of prostaglandin.
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