Cytokines nitric-oxide synthase induction

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]. 

The mechanistic basis of the neuroprotective activity of FAEE appears to rely not only on its general free-radical trapping or antioxidant activity per se, but also on its activity in mediating the induction of stress response proteins (HO-1 and F1SP72), cytoprotective (phase 2) proteins, and the parallel suppression of genes induced by pro-inflammatory cytokines, such as nitric oxide synthase (iNOS). 

Busse, R., and Mulsch, A. 1990. Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. FEBS Lett 275 87-90. 

Pahan K, Sheikh GF, Namboodiri AMS, Singh I (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microgha and macrophages. J Clin Invest 100 2671-2679. 

Kahl KG, Zielasek J, Uttenthal LO, Rodrigo J, Toyka KV, Schmidt HHHW (2003) Protective role of the cytokine-inducible isoform of nitric oxide synthase induction and nitrosative stress in experimental autoimmune encephalomyelitis of the DA rat. J Neurosci Res 73 198-205. 

NITRERGIC STIMULANTS mimic, or cause the production and release of nitric oxide (NO), which is an important mediator that is synthesized on demand. The actions of nitric oxide are very widespread, and imbalance is likely to be involved in a number of disease states. Nitric oxide synthase (NOS) has a widespread distribution in the body, and isoforms are recognized specifically constitutive and inducible (iNOS) forms. Both forms are cytosolic, Ca /calmodulin and NADPH-dependent, and inhibited by L-arginine derivatives. Induction of iNOS is by various inflammatory cytokines, particularly those stimulated by bacterial lipopolysaccarides, including tumour necrosis factor a. interferon 7 and interleukin 1 p. Induction of iNOS only is inhibited by GLUCOCORTICOIDS. 

Evidence for induction of inflammatory cytokines by organic solvents that induce the inducible nitric oxide synthase (iNOS). Elevated cytokines are an integral part of the proposed feedback mechanism of the elevated nitric oxide/peroxynitrite theory. 

The other broad category of MSP actions on macrophages relates to mediator production. Endotoxin, or combinations of proinflammatory cytokines, causes expression of murine macrophage-inducible nitric oxide synthase, an effect that can be detected by Northern blots for the mRNA or by measurement of nitrate in the culture fluid. MSP prevents induction of NO-synthase by any of the above stimuli (Wang et al., 1994d). The inhibitory action of MSP is confined to this specific mediator. MSP did not inhibit endotoxin-induced expression of mRNA for monocyte chemoattractant protein-1. Furthermore, MSP caused secretion of IL-6 (but not IL-1 or TNFa) within 6 hr, and did not inhibit endotoxin-induced secretion of IL-1, IL-6, or TNFa (A. Skeel and E. J. Leonard, unpublished data). The in vitro modulation by MSP of endotoxin-induced NO production now has an in vivo counterpart. Concentrations of nitrate in serum of Stk / mice that received endotoxin intravenously were higher than in serum of comparably treated normal mice and at a critical endotoxin dose, only 20% of the Stk / mice survived, compared to 80% survival for normal mice (Correll et al., 1997). If MSP plays a role in the host response to endotoxemia, pro-MSP must be cleaved to biologically active MSP. Within 4 hr after i.v. administration of... 

Koide, M., Kawahara, Y., Nakayama, I., Tsuda, T., and Yokoyama, M. (1993). Cyclic AMP-elevating agents induce an inducible type of nitric oxide synthase in cultured vascular smooth muscle cells Synergism with the induction elicited by inflammatory cytokines.. Biol. Chem. 268, 24959-24966. 

Bhat NR, Zhang P, Bhat AN. Cytokine induction of inducible nitric oxide synthase in an ohgodendrocyte cell line role of p38 mitogen-actiyated protein kinase actiyation. J Neurochem 1999 72(2) 472-478. 

It is synthesized from 1-arginine by nitric oxide synthase (NOS) (Moncada et al. 1991). There are two classes of NOS, constitutive NOS (neural type and endothelial type) and inducible NOS (iNOS). Generally, neural NOS and endothelial NOS, whieh are known to generate NO at low concentrations, are expressed constitutively in neurons and endothelial cells, respectively, and their activity depends on elevated intraeytoplasmic calcium/calmodulin levels. On the other hand, iNOS, which generates large amounts of NO for prolonged periods of time, is produced by neutrophils, macrophages, epithelial cells, and many other cell types, and induction of it requires bacterial products or inflammation-associated cytokines independent of calcium/calmodulin concentration (Nathan and Xie 1994 Knowles and Moncada 1994). 

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