title: Cyclooxygenase-2-regulated vascular endothelial growth factor release in gastric fibroblasts.
abstract: VEGF is a highly specific stimulator of endothelial cells and may play an important role in angiogenesis in the process of tissue regeneration. We previously showed that cyclooxygenase-2 (COX-2) expressed in mesenchymal cells of the ulcer bed is involved in the ulcer repair process. To clarify the role of COX-2 in angiogenesis during gastric ulcer healing, we investigated the relation between COX-2 expression and VEGF production in human gastric fibroblasts in vivo and in vitro. Gastric fibroblasts were cultured in RPMI 1640 with and without IL-1alpha or IL-1beta in the presence or absence of NS-398, a selective COX-2 inhibitor. Supernatant VEGF and PGE(2) concentrations were measured by enzyme-linked immunosorbent assay. COX-2 expression in fibroblasts was determined by Western blot analysis. VEGF and COX-2 expression in surgical resections of human gastric ulcer tissue was examined immunohistochemically. IL-1 dose dependently enhanced VEGF release in cultured gastric fibroblasts after a 24-h stimulation. IL-1 also stimulated PGE(2) production in gastric fibroblasts via COX-2 induction. NS-398 significantly suppressed VEGF and PGE(2) release from IL-1-stimulated gastric fibroblasts; concurrent addition of PGE(2) restored NS-398-inhibited VEGF release. COX-2 and VEGF immunoreactivity were colocalized in fibroblast-like cells in the ulcer bed of gastric tissues. These results suggest that COX-2 plays a key role in VEGF production in gastric fibroblasts stimulated by IL-1 in vitro and that angiogenesis induced by the COX-2-VEGF pathway might be involved in gastric ulcer healing.
authors.affiliation: Third Dept. of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Miura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tatsuguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Wada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takeyama
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shinji
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Hiratsuka
authors.forename: Seiji
authors.initials: S
authors.lastname: Futagami
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Miyake
authors.forename: Katya
authors.initials: K
authors.lastname: Gudis
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mizokami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Choitsu
authors.initials: C
authors.lastname: Sakamoto
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism / Q000502:physiology*; D013270:Stomach / Q000166:cytology; D013276:Stomach Ulcer / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone