Abstract
In the present study, we examined the effects of prostaglandin E1 (PGE1) on the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40, and CD40 ligand (CD40L) on peripheral blood mononuclear cells (PBMC) using fluorescence-activated cell sorting analysis as well as its effects on cytokine production using enzyme-linked immunosorbent assay. Whereas no inhibitor of spontaneous expression of adhesion molecules was reported, we found that PGE1 inhibited spontaneous ICAM-1, B7.2, and CD40 expression on monocytes in a concentration-dependent manner but had no effect on the expression of B7.1 and CD40L. Although interleukin (IL)-18 induced the expression of ICAM-1, B7.2, CD40, and CD40L, PGE1 prevented IL-18-induced expression of ICAM-1, B7.2, and CD40. We examined the involvement of five subtypes of PGE1 receptors (IP, EP1, EP2, EP3, and EP4) in the effect of PGE1 on the expression of these adhesion molecules using subtype-specific agonists. Among EP receptor agonists, EP2 and EP4 receptor agonists inhibited IL-18-elicited ICAM-1, B7.2, and CD40 expression. ONO-1301 (IP receptor agonist) prevented the expression of ICAM-1, B7.2, and CD40 regardless of the presence of IL-18 with the same potency as PGE1. The effect of a combination of ONO-1301 and 11-deoxy (D)-PGE1 (EP2/EP4 receptor agonist) on ICAM-1, B7.2, and CD40 expression mimicked that of PGE1. Moreover, PGE1 inhibited the production of IL-12 and interferon-γ in PBMC in the presence and absence of IL-18, whereas PGE1 induced IL-10 production. In conclusion, IP receptor and EP2/EP4 receptor play an important role in the action of PGE1 on the expression of adhesion molecules on monocytes and cytokine production.
Footnotes
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ABBREVIATIONS: ICAM, intercellular adhesion molecule; CD40L, CD40 ligand; IL, interleukin; IFN, interferon; NF-κB, nuclear factor-κB; PI, phosphatidylinositol; PGE1, prostaglandin E1; ONO-1301, 7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]aminooxy]ethyl]-1-naphthyoxy)acetic acid; ONO-DI-004, 17S-2,5-ethano-6-oxo-17,20-dimethyl prostaglandin E1; ONO-AE1-259-01, 11,15-O-dimethyl prostaglandin E2; ONO-AE-248, 16S-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro prostaglandin F2; ONO-AE1-329, 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia prostaglandin E1; CHO; Chinese hamster ovary; TNF, tumor necrosis factor; PBMC, peripheral blood mononuclear cells; 11-D-PGE1, 11-deoxy-PGE1; FITC, fluorescein isothiocyanate; mAb, monoclonal antibody; PE, phycoerythrin; CMC, class-matched control; Ab, antibody; fr., fraction; ELISA, enzyme-linked immunosorbent assay; LPS, lipopolysaccharide.
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This study was supported in part by a grant for Promotion of Research from Okayama University (No. 21 to M.N.), a grant from Okayama Medical Foundation (to H.K.T.) and grants from Grant-in-Aid for Scientific Research (C) (15590467 to H.K.T. and 15590228 to M.N.).
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DOI: 10.1124/jpet.103.056432.
- Received July 2, 2003.
- Accepted September 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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