Nitric Oxide Inhibits Lipopolysaccharide-Induced Inducible Nitric Oxide Synthase Expression and Its Own Production Through the cGMP Signaling Pathway in Murine Microglia BV-2 Cells

• Published in: Journal of Pharmacological Sciences Vol. 113; no. 2; pp. 153 - 160
• Main Authors: Yoshioka, Yasuhiro, Takeda, Nobuo, Yamamuro, Akiko, Kasai, Atsushi, Maeda, Sadaaki
• Format: Journal Article
• Language: English; Japanese
• Published: Japan Elsevier B.V 2010; The Japanese Pharmacological Society; Elsevier
• Subjects: Animals; Cells, Cultured; Cyclic GMP - physiology; Depression, Chemical; Dose-Response Relationship, Drug; guanosine-3′,5′-cyclic monophosphate (cGMP); inducible nitric oxide synthase (iNOS); Lipopolysaccharides - pharmacology; Mice; microglia; Microglia - enzymology; Microglia - metabolism; negative-feedback regulation; nitric oxide (NO); Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type II - metabolism; Signal Transduction - physiology; nitric oxide (NO); negative-feedback regulation; guanosine-3′,5′-cyclic monophosphate (cGMP); inducible nitric oxide synthase (iNOS); microglia
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.10060FP

The present study examined the effect of the nitric oxide (NO) donor NOC18 on lipopolysaccharide (LPS)-induced NO production to investigate a regulation mechanism of NO production by microglial cells. LPS increased the levels of NO and inducible NO synthase (iNOS) protein in BV-2 murine microglial cells in a concentration-dependent manner. Pretreatment with NOC18 for 24 h concentration-dependently attenuated the LPS-induced iNOS protein expression and NO production. The inhibitory effect of NOC18 on LPS-induced NO production was partially blocked by LY83583, a soluble guanylate cyclase inhibitor. Pretreatment with dibutyryl guanosine-3′,5′-cyclic monophosphate (DBcGMP), a cell-permeable cGMP analogue, for 24 h attenuated partially LPS-induced iNOS protein expression and NO production. Furthermore, the effects of LPS on iNOS and NO production were inhibited by the c-Jun N-terminal kinase (JNK) inhibitor SP600125, and LPS-induced phosphorylation of JNK and c-Jun was inhibited by NOC18 and DBcGMP. These results suggest that NO production by microglial cells is controlled by a negative feedback mechanism via the NO/cGMP signaling pathway.