title: Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1.
abstract: Prostacyclin synthase (PGIS) and microsomal prostaglandin E synthase-1 (mPGES-1) are prostaglandin (PG) terminal synthases that function downstream of inducible cyclooxygenase (COX)-2 in the PGI2 and PGE2 biosynthetic pathways, respectively. mPGES-1 has been shown to be involved in various COX-2-related diseases such as inflammatory diseases and cancers, but it is not yet known how PGIS is involved in these COX-2-related diseases. Here, to clarify the pathophysiological role of PGIS, we investigated the phenotypes of PGIS and mPGES-1 individual knockout (KO) or double KO (DKO) mice. The results indicate that a thioglycollate-induced exudation of leukocytes into the peritoneal cavity was suppressed by the genetic-deletion of PGIS. In the PGIS KO mice, lipopolysaccharide-primed pain nociception (as assessed by the acetic acid-induced writhing reaction) was also reduced. Both of these reactions were suppressed more effectively in the PGIS/mPGES-1 DKO mice than in the PGIS KO mice. On the other hand, unlike mPGES-1 deficiency (which suppressed azoxymethane-induced colon carcinogenesis), PGIS deficiency up-regulated both aberrant crypt foci formation at the early stage of carcinogenesis and polyp formation at the late stage. These results indicate that PGIS and mPGES-1 cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis, and that PGIS-derived PGI2 has anti-carcinogenic effects.
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kamiyama
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Kamiyama
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Konomi
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Akatsu
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuwata
authors.affiliation: Pathology Section, Itabashi Medical Laboratory, Tokyo 174-0051, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Department of Pathology, Saiseikai Yokohama City Tobu Hospital, Yokohama 230-8765, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Kanagawa Institute of Technology, Atsugi 243-0292, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Yokoyama
authors.affiliation: Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Hara
mesh_terms: D019342:Acetic Acid; D000818:Animals; D001397:Azoxymethane; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003111:Colonic Polyps / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics*; D015232:Dinoprostone / Q000096:biosynthesis; D011464:Epoprostenol / Q000096:biosynthesis; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071876:Prostaglandin-E Synthases; D013864:Thioglycolates
chemical_list: D008070:Lipopolysaccharides; D013864:Thioglycolates; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C022461:prostacyclin synthetase; D015232:Dinoprostone; D001397:Azoxymethane; D019342:Acetic Acid