Inducible nitric oxide synthase transcriptional activity

Evidence indicates exposure to nanoparticles can induce an inflammatory response in the CNS. For example, when a sample of mice were exposed to airborne particle matter, increased levels of pro-inflammatory cytokines (TNF-a IL-la), transcription factor, and nuclear factor-kappa beta (NF-k/3) were observed (114). TNF-a serves a neuroprotective function (115), but given certain pathogens TNF-a can be neurotoxic (116-120). IL-a activates cyclooxygenase (COX)-2, phospholipase A2, and inducible nitric oxide synthase (iNOS) activity, which are all associated with inflammation and immune response (121). IL-a is also partially responsible for increasing the permeability of the blood-brain barrier (122, 123). Thus, there is great interest in better understanding how nanoparticles enter the body and translocate as this will impact all organs and thus the toxicity of nanomaterials. 

In a rat type II pneumocyte analogue, the L2 cell line, exposed for 6 h to a combination of interferon-y (2,000 U/ml) and tumour necrosis factor-a (500 U/ml), extracellular superoxide dismutase and inducible nitric oxide synthase transcription was upregulated (Brady et al. 1997). Transcription of both genes was linked by activation of the transcription factor nuclear factor-xB. 

Saura, M., Zaragoza, C., Bao, C., McMillan, A., and Lowenstein, C.J. (1999). Interaction of interferon regulatory factor-1 and nuclear factor kappaB during activation of inducible nitric oxide synthase transcription. J. Mol. Biol. 289, 459-471. 

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. 

A major signalling pathway involves activation of a protein kinase that phosphorylates inhibitor kB proteins (IkBs) that normally inhibit the function of the nuclear transcription factor NFkB. Phosphorylation of IkB by the serine/threonine-specific IkB kinases (IKKs) leads to NFkB de-inhibition, nuclear translocation and expression of pro-inflammatory proteins such as inducible cyclooxygenase (iCOX) (which generates prostaglandins), inducible nitric oxide synthase (iNOS) (which generates vasodilatory and toxic free radicalgenerating NO) and pro-inflammatory cytokines. 

Rensing H, Jaeschke H, Bauer 1, Patau C, Datene V, Pannen BH and Bauer M, Differential activation pattern of redox-sensitive transcription factors and stress-inducible dilator systems heme oxygenase-1 and inducible nitric oxide synthase in hemorrhagic and endotoxic shock. Cril Care Med 29(10) 1962-71,2001. 

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. 

EGCG and theaflavins were found to inhibit xanthine oxidase (12,14) and suppress the production of ROS in HL-60 cells (12). EGCG and theaflavins inhibit nitric oxide production, which appears to be mediated through suppression of inducible nitric oxide synthase (iNOS), as demonstrated by its mRNA and protein levels (15,16). Electrophoretic mobility shift assay revealed that theaflavins and EGCG blunted activation of NFkB responsible for iNOS induction (15). These results indicate that these tea polyphenols inhibit the binding of NF /c B to iNOS promoter, thereby suppressing the transcription of iNOS gene. 

Suppression of Transcriptional Activity of Gene Promoter for Cyclooxygenase-2 and Inducible Nitric Oxide Synthase in Colon Cancer Cells... 

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