Nitric oxide responsive transcription factor

Seitzer et al. (1997) developed a new method for the in vitro generation of granulomas in which L3 larvae of Nippostrongylus brasiliensis were used as target for the cellular response of human mononuclear blood cells. Epithehoid cells and multinucle-ated giant cells developed. The presence of tumour necrosis factor-a, interleukin-ip, interleukin-6, and inducible nitric oxide synthase transcripts were demonstrated in multinucleated giant cells. 

The lack of zinc can also be a problem in biological systems and is responsible for disease states. For example, nitric oxide-dependent apoptosis can be induced in motor neurons by zinc-deficient SOD, and in some cases of amyotrophic lateral sclerosis, zinc-deficient SOD may participate in this type of oxidative mechanism involving nitric oxide.969 One form of hereditary human hair loss or alopecia was mapped to a specific gene and a mutation found in affected individuals. The gene encodes a single zinc finger transcription factor protein with restricted expression in the brain and skin.970 Zinc has been implicated in Alzheimer s via beta amyloid formation, and a role has been attributed for the cerebral zinc metabolism in the neuropathogenesis of Alzheimer s disease.971... 

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and have obtained preliminary evidence for nuclear factor RB (NF-kB) activation (J. A. Corbett and M. L. McDaniel, unpublished observation).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). 

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. 

The molecular mechanism linking the inflammatory response to redox equilibria and modification of nitric oxide production will be explored in an animal model system of septic shock, a generalized inflammation induced by bacterial lipopolisaccharide (LPS). It is known that endotoxemia induces a complex interplay between the activation of nuclear transcription factors such as nuclear factor kappa B (NFkB) and a cascade-activation of various enzymatic activities, mostly mediators of the inflammatory response with particular attention to the variation of the inducible form of nitric oxide synthase (iNOS). 

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. 

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