Nitric-oxide synthases transcriptional regulation

Lin, Y.L. and Lin, J.K., (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB, Mol Pharmacol, 52, 465, 1997. 

Micromolar quantities of RNS are generated primarily by nitric oxide synthase 2 (NOS2), an enzyme that is up-regulated during colon-cancer progression. As discussed below, deoxycholate (DOC), a hydrophobic secondary bile acid, activates the redox-sensitive transcription factor NF-kB, resulting in increased levels of NOS2 and enhanced S-nitrosylation of proteins. Additional sources of bile-acid-induced ROS and RNS are also likely. ... 

In addition we have shown that IL-1 also induces the expression of c-jun in both islets and RINm5F cells, and have obtained preliminary evidence for nuclear factor RB (NF-kB) activation (J. A. Corbett and M. L. McDaniel, unpublished observation). TTiese three transcriptional regulators alone or in combination are believed to participate in IL-1-induced expression of nitric oxide synthase by the islet j8 cell. Importantly, Nathan and co-workers have shown the presence of NF-kB response elements upstream of the mouse macrophage iNOS gene (Xie et cd., 1993). 

Siow RC, Li FY, Rowlands DJ, de Winter P, Mann GE. 2007. Cardiovascular targets for estrogens and phytoestrogens Transcriptional regulation of nitric oxide synthase and antioxidant defense genes. Free Radio Biol Med 42 909-925. 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

Tedeschi, E. et al. Green tea inhibits human inducible nitric-oxide synthase expression by down-regulating signal transducer and activator of transcription-1 alpha activation. Mol Pharmacol. 65, 111, 2004. 

Dlaska, M. and Weiss, G. 1999. Central role of transcription factor NF-IL6 for cytokine and iron-mediated regulation of murine inducible nitric oxide synthase expression. J Immunol 162 6171-6177. 

K. Cieslik, C.-M. Lee, J. Tang, K.K. Wu, Transcriptional regulation of endothelial nitric-oxide synthase by an interaction between casein kinase 2 and protein phosphatase 2A, J Biol Chem 274, 34669-34675 (1999). 

The Ca /calmodulin complex regulates the activity of many different proteins, including cAMP phosphodiesterase, nitric oxide synthase, and protein kinases or phosphatases that control the activity of various transcription factors. 

Tanacetum parthenium (Asteraceae), commonly known as feverfew, is a popular herbal remedy used a prophylactic in the treatment of migraine [88]. Studies have revealed that the action of feverfew is probably mediated by the sesquiterpene lactone parthenolide. Indeed, feverfew and parthenolide produce anti-inflammatory and antinociceptive effects in experimental animals [89]. Parthenolide is a potent inhibitor of the transcription factor NF-kB activation, a key regulator of pro-inflammatory protein production, such as cytokines, COX-2 and inducible nitric oxide synthase [90]. However, a clinical study revealed that feverfew did not provide any benefit in the treatment of rheumatoid arthritis [91]. Additional clinical studies must be carried out to explore the feverfew efficacy as an analgesic. 

---