Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1

Yuka Sasaki; Shuhei Kamiyama; Azusa Kamiyama; Konomi Matsumoto; Moe Akatsu; Yoshihito Nakatani; Hiroshi Kuwata; Yukio Ishikawa; Toshiharu Ishii; Chieko Yokoyama; Shuntaro Hara

doi:10.1038/srep17376

Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1

Sci Rep. 2015 Nov 27:5:17376. doi: 10.1038/srep17376.

Affiliations

¹ Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
² Pathology Section, Itabashi Medical Laboratory, Tokyo 174-0051, Japan.
³ Department of Pathology, Saiseikai Yokohama City Tobu Hospital, Yokohama 230-8765, Japan.
⁴ Kanagawa Institute of Technology, Atsugi 243-0292, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetic Acid
Animals
Azoxymethane
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinogenesis / pathology
Colonic Neoplasms / chemically induced
Colonic Neoplasms / genetics*
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Colonic Polyps / chemically induced
Colonic Polyps / genetics*
Colonic Polyps / metabolism
Colonic Polyps / pathology
Cyclooxygenase 2 / genetics*
Cyclooxygenase 2 / metabolism
Cytochrome P-450 Enzyme System / deficiency
Cytochrome P-450 Enzyme System / genetics*
Dinoprostone / biosynthesis
Epoprostenol / biosynthesis
Intramolecular Oxidoreductases / deficiency
Intramolecular Oxidoreductases / genetics*
Lipopolysaccharides / pharmacology
Macrophages, Peritoneal / drug effects
Macrophages, Peritoneal / metabolism
Macrophages, Peritoneal / pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Nociception / drug effects
Pain / chemically induced
Pain / genetics*
Pain / metabolism
Pain / pathology
Peritonitis / chemically induced
Peritonitis / genetics*
Peritonitis / metabolism
Peritonitis / pathology
Prostaglandin-E Synthases
Thioglycolates

Substances

Lipopolysaccharides
Thioglycolates
Cytochrome P-450 Enzyme System
Epoprostenol
Ptgs2 protein, mouse
Cyclooxygenase 2
Intramolecular Oxidoreductases
Prostaglandin-E Synthases
Ptges protein, mouse
prostacyclin synthetase
Dinoprostone
Azoxymethane
Acetic Acid