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Nitric oxide (NO) was discovered over twenty years ago to be a molecule that was biologically active and ever since documented as one of the most versatile components of the immune system. NO is a readily diffusible gas that mediates cell-cell communication and thus has been branded as a universal messenger. It is particularly interesting as it is part of the pathogenesis as well as the control of infectious diseases, along with autoimmunity, neurodegenerative diseases and cancers. NO can be formed from one of the three NO synthases, two of which are essentially expressed in the body: endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS). The third being inducible NOS (iNOS) where production is most commonly stimulated by proinflammatory markers.1,2,3 This essay will evaluate the role of nitric oxide with the immune system on a biological level using the most current literature available to make its potential role clearer. The other uses of nitric oxide and its current clinical implications are outside the scope of this essay, along with investigation into cancer due to size restraint.
A variety of searches were used to find the literature needed, including PubMed, Google scholar and the Cochrane library using the keywords 'Nitric Oxide Immune system', 'NO immune' and 'role NO immune'. The Cochrane search returned no relevant results and pubmed and google scholar were used to retrieve specific studies and one uncited systematic review.. The potentially relevant articles were identified through matching the keywords. Then exclusion criteria such as relevance, being well cited and date published were employed. Initially there were many articles found in the searches but these were found to be unhelpful and irrelevant due to the nature of their results and research prospective.
NO is formed following enzyme activation of an Nitric oxide synthase, this is done by the conversion of L-arginine to citrulline. The eNOS and nNOS are found in certain places not relating to their names. nNOS is found in high levels in the central nervous system testicles and skeletal muscle, where it is involved with skeletal muscle contraction and platelet aggregation.2,3 eNOS regulates vascular reactivity in the periphery and the brain as it is associated with the Golgi in the endothelial cells.4 Activation of the NO synthases is firstly brought about by Ca2+ fluxes and then binding on calmodulin.5 iNOS, which is induced very quickly in large amounts by such things as cytokines and endotoxin, does not need an flux in Ca2+ to activate.2,4 NO is free radical and therefore prolonged exposure to large amounts of nitric oxide and inhibit enzymes causing potential cytoxicity and the formation of pathogenesis.6 this review will focus on these pathogenic reactions to NO and their causes along with a look into the NOS synthathes interactions within the immune cells.
How is NO produced in the Immune system?
The paper by Bogdan, 2001 states that it is uncertain whether primary T or B lymphocytes express the NOS isoforms, but iNOS and eNOS have been found in mast cells, macrophages, natural killer cells and phagocytic cells and this shows that NO is an essential component of many immune cells so more research should be directed here.3,5 In a study by Relling, 1996 PCR methods were used to detect NOS mRNA within T cells, this had a higher risk of false positives which reduced the sensitivity of the testing because of cell contamination so eventhough it is not as reliable it did show that NOS existed within T cells where as all previous research had been looking into the roles of such cells as macrophages in the production of NO.3,6,7 Unlike eNOS and nNOS, iNOS mRNA has to the produced under a specific stimulus, and 'the gene promoter for this gives the parameters under the effect of cytokines'.3,8 iNOS expression is dependent on different signalling pathways which either promote or block expression. A study carried out by Musial and Eissa (2001) showed that iNOS esxpression was suppressed by some compounds by blocking degradation where as in a study by Coleman (2001) NO was shown to be able to regulate its own production. It was shown that in a positive feedback loop, macrophage stimulation by cytokines when NO was reduced it was upregulated and iNOS was produced, where as when NO was high a negative feedback loop was observed which could be due to a mechanism prevention overproduction of NO due to its related pathologies. 3,9,10 Both these studies are very highly reviewed by their peers, and are both very credible sources form respected experts in the field but yet present showing that yet still more needs to be done to define the NO pathways and a definitive study must be taken.
What is the role of NO in infection and inflammation?
'NO plays a crucial role at all stages of infection and it has a diverse and somewhat contradictory spectrum of activities.'3
This is certainly true and shown in several studies involving iNOS deficient mice and the immunological effects mediated by NO including Rollinghoff et al. (2000) which described the functions of NO as 'antiviral, antimicrobial, immunostimulatory, immunosuppressive, cytotoxic and cytoprotective.'11 There are several mechanisms by which the antimicrobial powers of NO might occur, suggested by Bogdan (2001) to be mutation of DNA, inhibition of DNA repair and synthesis, alteration of proteins and enzyme inactivation. 3,5 In another study, Dalton et al. (2000), showed further iNOS dependant effects such as the termination of the immune response of activated CD4+ T cells by apoptosis and the inhibition of tissue fibrosis.
It was also shown by Kroncke et al (1998) and then by Iniesta et al (2001) that bacterium and parasites were killed in vitro by NO by activated macrophages. The studies showed that it was an intermediate in the iNOS-NO pathway that contributed to the killing of the parasite by blocking arginase activity.13, 14,
In contrast to these beneficial effects to the body from NO when dealing with infection it is known to show pathogenic tendancies when at high concentrations.15 Nitric oxide has been shown to mediated cytotoxicity and tissue death, and Bogdan (2001) states the inhibition of T cell proliferation and induction of T cell apoptosis. 3,5 While also 'have direct positive effects on viral or microbial growth.'3 (supported by Bogdan, 20015). NO being produced in large amounts cause the production of large amounts of superoxide anion which then join together to form peroxynitrite. This is a mediator of NO that is Cytotoxic, and this can cause a complete reversal in the protective effects of NO. These products target proteins and enzymes which are cruitial for cell survival due to interfering with cell signalling.1,10,15
The sources used in this essay are all very well sought out, the one systematic review (Hosking, 2009)3 has played a crucial part gathering information from the studies and reliable source while it not being a very credible source of information itself not being peer review or cited, it took the direct information needed from the sources and therefore must be credited. The information in the other studies may be contrived but it is all yet reliable, even though the sources present with contradicting information. Especially (Bogdan, 2001) which shows both aspects but is presented very well with the information showing NO's properties that play an aiding role in the immune system followed by those that have the complete reverse effects, this has shown to be a very good source of information.
From the evidence shown the conclusion drawn in that there definitely is a role for Nitric oxide in the immune system, and a critical role at that, but not enough research has yet been done to show which of the aspects are greater and whether it can he harnessed to be used in a clinical scenario. While NO is an anti-microbial molecule, it can at the very same time cause tissue death, while NO is very specific from what is shown so far it isn't controllable and so this is where more research studies should be carried out, into how to isolate certain properties of the NO and iNOS and the pathways themselves so that they can be specifically targeted in order to become useful and develop the role of NO as a treatment and/or support for the immune system. The literature showed that NO has many host protective effects especially during invasion by infectious agents. However the over stimulation of Nitric oxide synthases can be far more damaging causing inflammatory pathologies, tissue death and cell apoptosis. 1-15
Within the limitations of this essay only a brief report can be given on the role of nitric oxide within the immune system as no study or systematic review has been undertaken. In the future it would be more helpful to perform a more detail report of each aspect for example the production of NO as a result of the stimulus of proinflamatory mediators and the possible benefits. In a field that is advancing so fast there will undoubtedly be fascinating research in the near future.