title: Novel regulatory mechanisms of CD40-induced prostanoid synthesis by IL-4 and IL-10 in human monocytes.
abstract: Interleukins IL-4 and IL-10 are considered to be central regulators for the limitation and eventual termination of inflammatory responses in vivo, based on their potent anti-inflammatory effects toward LPS-stimulated monocytes/macrophages and neutrophils. However, their role in T cell-dependent inflammatory responses has not been fully elucidated. In this study, we investigated the effects of both cytokines on the production of PGE(2), a key molecule of various inflammatory conditions, in CD40-stimulated human peripheral blood monocytes. CD40 ligation of monocytes induced the synthesis of a significant amount of PGE(2) via inducible expression of the cyclooxygenase (COX)-2 gene. Both IL-10 and IL-4 significantly inhibited PGE(2) production and COX-2 expression in CD40-stimulated monocytes. Using specific inhibitors for extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), we found that both kinase pathways are involved in CD40-induced COX-2 expression. CD40 ligation also resulted in the activation of NF-kappaB. Additional experiments exhibited that CD40 clearly induced the activation of the upstream kinases MAPK/ERK kinase 1/2, MAPK kinase 3/6, and I-kappaB in monocytes. IL-10 significantly inhibited CD40-induced activation of the ERK, p38 MAPK, and NF-kappaB pathways; however, inhibition by IL-4 was limited to the ERK pathway in monocytes. Neither IL-10 nor IL-4 affected the recruitment of TNFR-associated factors 2 and 3 to CD40 in monocytes. Collectively, IL-10 and IL-4 use novel regulatory mechanisms for CD40-induced prostanoid synthesis in monocytes, thus suggesting a potential role for these cytokines in regulating T cell-induced inflammatory responses, including autoimmune diseases.
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otsuka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Shuji
authors.initials: S
authors.lastname: Nagano
authors.forename: Yojirou
authors.initials: Y
authors.lastname: Arinobu
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ogami
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Akahoshi
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Miyake
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ninomiya
authors.forename: Sakiko
authors.initials: S
authors.lastname: Shimizu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D021381:Protein Transport / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D002352:Carrier Proteins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007527:Isoenzymes; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D009578:Nitrobenzenes; D011725:Pyridines; D011994:Recombinant Proteins; D012097:Repressor Proteins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016753:Interleukin-10; D015847:Interleukin-4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one