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Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1.
- Source :
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Scientific reports [Sci Rep] 2015 Nov 27; Vol. 5, pp. 17376. Date of Electronic Publication: 2015 Nov 27. - Publication Year :
- 2015
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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.
- Subjects :
- Acetic Acid
Animals
Azoxymethane
Carcinogenesis genetics
Carcinogenesis metabolism
Carcinogenesis pathology
Colonic Neoplasms chemically induced
Colonic Neoplasms metabolism
Colonic Neoplasms pathology
Colonic Polyps chemically induced
Colonic Polyps metabolism
Colonic Polyps pathology
Cyclooxygenase 2 metabolism
Cytochrome P-450 Enzyme System deficiency
Dinoprostone biosynthesis
Epoprostenol biosynthesis
Intramolecular Oxidoreductases deficiency
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 metabolism
Pain pathology
Peritonitis chemically induced
Peritonitis metabolism
Peritonitis pathology
Prostaglandin-E Synthases
Thioglycolates
Colonic Neoplasms genetics
Colonic Polyps genetics
Cyclooxygenase 2 genetics
Cytochrome P-450 Enzyme System genetics
Intramolecular Oxidoreductases genetics
Pain genetics
Peritonitis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 5
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 26611322
- Full Text :
- https://doi.org/10.1038/srep17376