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Genomic and lipidomic analyses differentiate the compensatory roles of two COX isoforms during systemic inflammation in mice.

ABSTRACT: Both cyclooxygenase (COX)-1 and COX-2, encoded by Ptgs1 and Ptgs2, function coordinately during inflammation. But the relative contributions and compensations of COX-1 and COX-2 to inflammatory responses remain unanswered. We used three engineered mouse lines where the Ptgs1 and Ptgs2 genes substitute for one another to discriminate the distinct roles and interchangeability of COX isoforms during systemic inflammation. In macrophages, kidneys, and lungs, "flipped" Ptgs genes generate a "reversed" COX expression pattern, where the knock-in COX-2 is expressed constitutively and the knock-in COX-1 is lipopolysaccharide inducible. A panel of eicosanoids detected in serum and kidney demonstrates that prostaglandin (PG) biosynthesis requires native COX-1 and cannot be rescued by the knock-in COX-2. Our data further reveal preferential compensation of COX isoforms for prostanoid production in macrophages and throughout the body, as reflected by urinary PG metabolites. NanoString analysis indicates that inflammatory networks can be maintained by isoform substitution in inflamed macrophages. However, COX-1>COX-2 macrophages show reduced activation of inflammatory signaling pathways, indicating that COX-1 may be replaced by COX-2 within this complex milieu, but not vice versa. Collectively, each COX isoform plays a distinct role subject to subcellular environment and tissue/cell-specific conditions, leading to subtle compensatory differences during systemic inflammation.

SUBMITTER: Li X

PROVIDER: S-EPMC5748501 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Genomic and lipidomic analyses differentiate the compensatory roles of two COX isoforms during systemic inflammation in mice.

Li Xinzhi X Mazaleuskaya Liudmila L LL Ballantyne Laurel L LL Meng Hu H FitzGerald Garret A GA Funk Colin D CD

Journal of lipid research 20171127 1

Both cyclooxygenase (COX)-1 and COX-2, encoded by Ptgs1 and Ptgs2, function coordinately during inflammation. But the relative contributions and compensations of COX-1 and COX-2 to inflammatory responses remain unanswered. We used three engineered mouse lines where the Ptgs1 and Ptgs2 genes substitute for one another to discriminate the distinct roles and interchangeability of COX isoforms during systemic inflammation. In macrophages, kidneys, and lungs, "flipped" ...[more]

PMID: 29180443

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Dataset Information

Genomic and lipidomic analyses differentiate the compensatory roles of two COX isoforms during systemic inflammation in mice.

Publications

Genomic and lipidomic analyses differentiate the compensatory roles of two COX isoforms during systemic inflammation in mice.

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