Cytokines inducible nitric-oxide synthases

D16. De Vera, M. E Kim, Y. M., Wong, H. R Wang, Q Billiar, T. R., and Geller, D. A., Heat shock response inhibits cytokine-inducible nitric oxide synthase expression in rat hepatocytes. Hepatology 24,1238-1245 (1996). 

Ulisse, S., Gionchetti, P, D Alo, S. et al. 2001. Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinases in pouchitis Effects of probiotic treatment. Am J Gastroenterol 96 2691-2699. 

Wood, E. R., Berger, H. J., Sherman, P. A., and Lapetina, E. G. (1993). Hepatocytes and macrophages express an identical cytokine inducible nitric oxide synthase gene. Biochem. Biophys. Res. Commun. 191, 767-774. 

Berge, DT., Ridder, M.D., Verovski, V.N., Janssens, M.Y., Monsaert, C., and Storme, G.A. (2001). Chronic hypoxia modulates tumour cell radioresponse through cytokine-inducible nitric oxide synthase. Br. J. Cancer 84, 1122-1125. 

Exposure to trichothecenes at levels that partially inhibit translation upregulates expression of many inflammatory and immune-related genes including macrophage, Thl and Th2 cytokines as well as chemokines, cyclooxygenase 2 and inducible nitric oxide synthase.1518 Contrastingly, suppressive effects of trichothecenes on leukocyte function are intimately linked with the induction of apoptosis as has been demonstrated in macrophages, T cells and B cells both in vivo and in vitro.19-20... 

To set up and validate the in vitro systems we initiated a study with rat Uver slices. Stimulation by Upopolysaccharide (LPS) in liver slices was used to evoke a pro-inflammatory response in the Uver. Lipopolysaccharide (LPS), a component of Gram-negative bacterial ceU walls (also called endotoxin), has been associated with tissue injury and sepsis. In the Uver LPS activates the resident macrophages, the Kupffer ceUs, which results in cytokine release [96]. Furthermore, LPS is cleared by the Uver, mainly by Kupffer ceUs [97]. One of the major features of endotoxic shock is the induction of nitric oxide S5mthase in the Uver [98]. Inducible nitric oxide synthase (iNOS), the expression of which is induced by LPS and cytokines, produces nitric oxide (NO) in large quantities [99]. 

Isolated cells from infected mice are less proliferative upon in-vitro activation and increase inducible nitric oxide synthase expression in peritoneal cells, yet splenocytes have normal cytokine responses to ConA (Dai and Gottstein, 1999)... 

Heneka, M. T., Feinstein, D., Galea, E., Gleichmann, M., Wullner, U., and Klockgether, T. (1999). Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J. Neuroim-munol. 100, 156-168. 

Maggi, L. B.Jr., Sadeghi, H., Weigand, C., Scarim, A. L., Heitmeier, M. R., and Corbett, J. A. (2000). Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone Evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. Diabetes 49, 346-355. 

Miller KJ, Gonzalez HA. Serotonin 5-HT2A receptor activation inhibits cytokine-stimulated inducible nitric oxide synthase in C6 glioma cells. Ann NY Acad Sci 1998 861 169-173. 

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. 

Bisphosphonates (particularly clodronate) have been shown to have anti-inflammatory effects in animal models of rheumatoid arthritis (RA), as well as in arthritis in humans. In adjuvant- and antigen-induced arthritis in rats, clodronate suppresses the inflammatory articular lesions in the inflamed joints [29], whilst in human RA, clodronate decreases the levels of interleukin (ILJ-1, tumor necrosis factor-alpha (TNFaand /1-microglobulin in the circulation [30]. In vitro, clodronate inhibits cytokine and nitric oxide (NO) release and inducible nitric oxide synthase (iNOS) expression in macrophage-like cells. 

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. 

There are three major isoforms of nitric oxide synthase (NOS). The first to be described is termed inducible, because inflammatory agents such as endotoxin and/or cytokines trigger the de novo transcription and translation of inducible nitric oxide synthase (iNOS) molecules. It is likely that, at least in rodents, every nucleated cell is capable of being triggered to produce iNOS the different sensitivities to signals probably lie only in the differing mechanisms of signal transduction between cell types. 

Jana M, Anderson JA, Saha RN, Liu X, Pahan K (2005) Regulation of inducible nitric oxide synthase in proinflammatory cytokine-stimulated human primary astrocytes. Free Radic Biol Med 38 655-664. 

The innate pro-inflammatory response of these cells is activated upon exposure to LPS, prostaglandin or other TLR ligands, leading to production of classical proinflammatory cytokines including tumor necrosis factor (TNF)-a. On the other hand, classical activation by interferon (fFN)- /andLPS leads to production of TNF-a and also increased secretion of reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). 

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