ReviewNitric oxide in immunity and inflammation
Introduction
Nitric oxide (NO) is a molecule utilised throughout the animal kingdom as a signalling or toxic agent between cells. Generated by many cell types in a variety of tissues, in mammals it acts as a vascular relaxing agent, a neurotransmitter and an inhibitor of platelet aggregation [1], [2]. In addition to these physiological roles, NO is generated during immune and inflammatory responses—here its function is less well defined and more complex [1], [2]. It is involved in innate immunity as a toxic agent towards infectious organisms, but can induce or regulate death and function of host immune cells, thereby regulating specific immunity. NO may induce toxic reactions against other tissues of the host and since it is generated at high levels in certain types of inflammation, for example asthma, it has been implicated as a pro-inflammatory agent. Equally, it may act as an anti-inflammatory or immunosuppressive agent via its inhibitory or apoptotic effects on cells.
The role of NO in immunity and inflammation and its mechanisms of action in these processes will be the subject of this review and the other articles in this issue of International Immunopharmacology. Before considering NO in immunity and inflammation, it is important to understand basic aspects of its synthesis, chemistry and reactivity with biological molecules.
Section snippets
Synthesis of nitric oxide
NO is synthesised universally from l-arginine and molecular oxygen by an enzymatic process that utilises electrons donated by NADPH. The NO synthase (NOS) enzymes convert l-arginine to NO and l-citrulline via the intermediate N-hydroxy-l-arginine. One molecule of l-arginine produces one molecule of NO, the nitrogen atom of the latter deriving from a terminal guanidino group of the arginine side chain.
There are three types of NOS. Two of these are constitutively expressed while the other is
Biological chemistry of nitric oxide
Nitric oxide is a simple diatomic molecule whose physico-chemical and biological properties are determined by its small size (30 Da), absence of charge and its single unpaired electron. NO is a gas under atmospheric conditions but a solute within cells and tissues. Its solubility and diffusion properties resemble closely those of oxygen. It is readily diffusible in body fluids and tissues and freely crosses cell membranes. Its lone outer electron renders it a radical and therefore chemically
Nitric oxide in immunity
NO plays several roles in immunity—as a toxic agent towards infectious organisms [12], [13], [14], an inducer or suppressor of apoptosis [11] or an immunoregulator [15], [16], [17], [18], [19], [20], [21], [22]. Basic considerations point to NOS-2 as the likely NOS isoform involved in the immune response. Because the immune system is activated in response to infection, any associated NO response would develop in parallel, over days or weeks rather than within a fraction of a second as in
Nitric oxide in inflammation and asthma
As reviewed elsewhere in this issue [17], NO is generated at high levels during human inflammatory reactions such as asthma [33] and, as in the immune response, the principal NOS isotype involved is NOS-2 [34]. Although the majority of mediators generated during inflammation, such as IFN-γ, TNF-α, leukotrienes and most prostaglandins, are pro-inflammatory, others such as the cyclopentanone prostaglandins are anti-inflammatory [35]. Therefore, any mediator generated during inflammation cannot be
Regulation of cell death by nitric oxide
As described in two articles in this issue [11], [49], NO regulates death of immune cells, either through induction or inhibition of apoptosis, or by necrosis. In addition, NO can mediate killing of tissue-specific cells in immunologically mediated diseases. For example, NO production by macrophage NOS-2 is responsible for the killing of β-islet cells in a rodent model of autoimmune diabetes [50]. These cells enter into the early stages of apoptosis, but subsequent energy and ATP depletion of
Nitric oxide target selectivity—relevance to immunity
NO is unusual as a signalling molecule since it has no cell surface receptor but enters cells indiscriminately. Its biological selectivity depends on: (1) its concentration and reactivity with other molecules, (2) the proximity of target cells, and (3) the way in which the target cell is programmed to respond. Another important question is how the source cell protects itself from NO. Bearing in mind that the half-life of NO increases markedly as its concentration decreases [8]. Its effects,
Nitric oxide signalling in the immune system
Biological signalling by NO can be classified into direct and indirect actions (Fig. 1) and it is almost certainly the latter that are most important in the immune system.
The direct actions of NO occur at low concentrations, as generated by the constitutive nitric oxide synthases NOS-1 and NOS-3. Here, NO is not readily oxidised and interacts directly with positively charged metal ions in proteins, for example the iron atom in the heme moiety of hemoglobin, myoglobin, guanylyl cyclase,
Conclusions
NO is generated, largely by the NOS-2 enzyme, in many cell types involved in immunity and inflammation. It exerts complex regulatory activity on the function, growth and death of many immune and inflammatory cell types both in vitro and in vivo. The signalling processes through which NO acts to regulate these cells are extremely complex and are only just beginning to be unraveled, but are largely indirect (Fig. 1) through generation of reactive nitrogen oxide species that chemically modify
Acknowledgements
The author's work is supported by the Medical Research Council and The Wellcome Trust.
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