Inhibition of cyclooxygenase-2 by natriuretic peptides.
The atrial natriuretic peptide (ANP) has been suggested to possess immunomodulatory potential because of its property to alter macrophage functions via its guanylate-cylcase- coupled A-receptor (NPR-A), such as inhibiting the expression of inducible nitric oxide synthase or TNF-alpha. The aim of this study was to investigate whether ANP influences COX-2. COX-2 expression in murine macrophages and in mice was induced by lipopolysaccharide. Release of PGE(2) and thromboxane B(2) was significantly reduced in the presence of ANP. C-type natriuretic peptide (CNP) also significantly reduced PGE(2)-accumulation in macrophages. Northern and Western blots showed that ANP attenuates COX-2 mRNA and protein. Reduction of neither COX-2 nor of PGE(2) production was significantly abrogated by an NPR-A antagonist, suggesting a pathway independent of cGMP. Furthermore, dibutyryl-cGMP did not affect PGE(2)-accumulation. cANF, the specific ligand for the natriuretic peptide (NP) clearance-receptor (NPR-C), significantly inhibited PGE(2)-production. Because some biological activities of ANP have been reported to be mediated via an NPR-C-mediated inhibition of adenylate-cyclase, we determined cAMP levels. ANP, CNP, and cANF significantly attenuated intracellular cAMP. In summary, ANP was shown to attenuate PGE(2)-production of lipopolysaccharide-activated macrophages predominantly via the NP clearance-receptor. ANP reduces COX-2-protein and -mRNA levels. The inhibition seems to be mediated via NPR-C and related to an attenuation of cAMP production.
Kiemer
Alexandra K
AK
Department of Pharmacy, Center of Drug Research, University of Munich, 81377 Munich, Germany. alexandra.kiemer@cup.uni-muenchen.de
Lehner
Martin D
MD
Hartung
Thomas
T
Vollmar
Angelika M
AM
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D007527:Isoenzymes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects / Q000502:physiology; D013929:Thromboxane B2 / Q000096:biosynthesis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D013929:Thromboxane B2; D009320:Atrial Natriuretic Factor; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017461:Receptors, Atrial Natriuretic Factor; D015232:Dinoprostone