Review
Nitric oxide in immunity and inflammation

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Abstract

Nitric oxide (NO) is synthesised by many cell types involved in immunity and inflammation. The principal enzyme involved is the inducible type-2 isoform of nitric oxide synthase (NOS-2), which produces high-level sustained NO synthesis. NO is important as a toxic defense molecule against infectious organisms. It also regulates the functional activity, growth and death of many immune and inflammatory cell types including macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils and natural killer cells. However, the role of NO in nonspecific and specific immunity in vivo and in immunologically mediated diseases and inflammation is poorly understood. NO does not act through a receptor—its target cell specificity depends on its concentration, its chemical reactivity, the vicinity of target cells and the way that target cells are programmed to respond. At high concentrations as generated by NOS-2, NO is rapidly oxidised to reactive nitrogen oxide species (RNOS) that mediate most of the immunological effects of NOS-2-derived NO. RNOS can S-nitrosate thiols to modify key signalling molecules such as kinases and transcription factors. Several key enzymes in mitochondrial respiration are also inhibited by RNOS and this leads to a depletion of ATP and cellular energy. A combination of these interactions may explain the multiple actions of NO in the regulation of immune and inflammatory cells.

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.

References (60)

  • P.J. Barnes et al.

    Nitric oxide and asthmatic inflammation

    Immunol. Today

    (1995)
  • P. Forsythe et al.

    Mast cells and nitric oxide: control of production, mechanisms of response

    Int. Immunopharmacol.

    (2001)
  • M. Bidri et al.

    Mast cells as a source and target for nitric oxide

    Int. Immunopharmacol.

    (2001)
  • R. Armstrong

    The physiological role and pharmacological potential of nitric oxide in neutrophil activation

    Int. Immunopharmacol.

    (2001)
  • R.C. van der Veen et al.

    Nitric oxide inhibits the proliferation of T-helper 1 and 2 lymphocytes without reduction in cytokine secretion

    Cell Immunol.

    (1999)
  • S.A. Kharitonov et al.

    Increased nitric oxide in exhaled air of asthmatics

    Lancet

    (1994)
  • R.A. Robbins et al.

    Expression of inducible nitric oxide in human lung epithelial cells

    Biochem. Biophys. Res. Commun.

    (1994)
  • R. Ross et al.

    The role of nitric oxide in contact hypersensitivity

    Int. Immunopharmacol.

    (2001)
  • M. Kimura et al.

    Mast cell degranulation in rat mesenteric venule: effects of l-NAME, methylene blue, and ketotifen

    Pharmacol. Res.

    (1999)
  • M. Miura et al.

    Endogenous nitric oxide modifies antigen-induced microvascular leakage in sensitized guinea pig airways

    J. Allergy Clin. Immunol.

    (1996)
  • M.G. Belvisi et al.

    Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in human airways

    Eur. J. Pharmacol.

    (1992)
  • P.K.M. Kim et al.

    The regulatory role of nitric oxide in apoptosis

    Int. Immunopharmacol.

    (2001)
  • K.D. Kröncke et al.

    Pancreatic islet cells are highly susceptible towards the cytotoxic effects of chemically generated nitric oxide

    Biochim. Biophys. Acta

    (1993)
  • H. Schindler et al.

    Nitric oxide as a signalling molecule: effects on kinases

    Int. Immunopharmacol.

    (2001)
  • G. Brown

    Nitric oxide and mitochondrial respiration

    Biochim. Biophys. Acta

    (1999)
  • S. Mohr et al.

    Nitric oxide-induced S-nitrosylation and inactivation of glyceraldehyde-3-phosphate dehydrogenease

    J. Biol. Chem.

    (1999)
  • H.M. Lander et al.

    A molecular redox switch on p21ras

    J. Biol. Chem.

    (1997)
  • S. Wang et al.

    A Sp1 binding site of the tumor necrosis factor α promoter functions as a nitric oxide response element

    J. Biol. Chem.

    (1999)
  • S. Moncada et al.

    Nitric oxide: physiology, pathology and pharmacology

    Pharmacol. Rev.

    (1991)
  • J. Lincoln et al.

    Nitric oxide in health and disease

    (1997)
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