Cyclooxygenase-2-dependent prostaglandin E2 down-regulates intercellular adhesion molecule-1 expression via EP2/EP4 receptors in interleukin-1beta-stimulated human gingival fibroblasts.
Prostaglandin E2 (PGE2), which exerts its actions via EP receptors (EP1, EP2, EP3, and EP4), is a bioactive metabolite of arachidonic acid produced by cyclooxygenase (COX)-1 and/or COX-2. We have previously demonstrated that PGE2 down-regulates intercellular adhesion molecule-1 (ICAM-1) expression in interleukin-1beta (IL-1beta)-stimulated human gingival fibroblasts (HGF). In the present study, we investigated which COX was involved in down-regulation of ICAM-1 expression by PGE2 in IL-1beta-stimulated HGF and which subtypes of EP receptors modulated the ICAM-1 expression. NS-398, a specific COX-2 inhibitor, completely inhibited PGE2 production by IL-1beta-stimulated HGF, as did indomethacin, a COX-1/COX-2 inhibitor. Northern blot analysis and immunocytochemical staining showed that mRNA and protein of COX-2 were expressed in IL-1beta-challenged HGF, but not in unstimulated HGF, and that the expression of mRNA and protein of COX-1 was similar both in unstimulated and in stimulated cells. NS-398 and indomethacin enhanced ICAM-1 expression in IL-1beta-challenged HGF. EP1, EP2, and EP4 receptor mRNA was expressed in HGF according to reverse-transcription/polymerase chain-reaction. PGE2, 11-deoxy-PGE1 (a selective EP2/EP4 agonist), and Butaprost (a selective EP2 agonist) attenuated IL-1beta-elicited ICAM-1 expression, although Butaprost was less potent than PGE2 and 11-deoxy-PGE1. AH-23848B, an EP4 antagonist, antagonized the inhibitory effect of IL-1beta-elicited ICAM-1 expression by PGE2. Sulprostone, an EP1/EP3 agonist, had no effect on IL-1beta-elicited ICAM-1 expression. Analysis of these data suggests that COX-2-derived PGE2 down-regulates ICAM-1 expression via EP2/EP4 receptors in IL-1beta-stimulated HGF.
Noguchi
K
K
Periodontology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Japan. kazuyuki-noguchi.peri@dent.tmd.ac.jp
Iwasaki
K
K
Shitashige
M
M
Endo
H
H
Kondo
H
H
Ishikawa
I
I
D000704:Analysis of Variance; D015152:Blotting, Northern; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology*; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology* / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017077:Culture Media, Conditioned; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018799:Intercellular Adhesion Molecule-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone