Chapter 22 : Regulation and Antimicrobial Function of Inducible Nitric Oxide Synthase in Phagocytes

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This chapter discusses the regulation and antimicrobial function of inducible nitric oxide synthase (iNOS) in phagocytes. The focus is on more recent aspects of the expression of iNOS in macrophages, the molecular mechanisms of iNOS-dependent control of infectious pathogens, and the cross-regulation of iNOS and arginase. iNOS induction and suppression in macrophages are regulated at multiple levels: gene transcription, mRNA stability, mRNA translation, protein stability, and substrate availability. One of the key functions of iNOS, its product nitric oxide (NO), and its oxidation products (collectively termed reactive nitrogen intermediates [RNIs]) is the antimicrobial activity, which, from an operational point of view, can be divided into four major categories, as follows, (i) Direct (‘‘toxic’’) effects of NO on structural components, the replication machinery, nucleic acids, virulence factors, metabolic enzymes, and pathways of infectious pathogens, (ii) iNOS-dependent antimicrobial effects that are independent of its product NO, (iii) NO-mediated inhibition of microbial evasion and resistance mechanisms, and (iv) immunostimulatory function of NO. Importantly, the cytotoxic function of NO and peroxynitrite is not restricted to pathogens, but may also extend to host cells. Today, we know that even the antimicrobial activity of iNOS in macrophages can originate from various direct or indirect processes that do not necessarily require high-output generation of NO. Furthermore, the interplay between iNOS and arginase has led to additional layers of regulation and function. The long-desired therapeutic application of NO donors and arginase inhibitors only begins to emerge.

Citation: Bogdan C. 2009. Regulation and Antimicrobial Function of Inducible Nitric Oxide Synthase in Phagocytes, p 367-378. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch22
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Image of FIGURE 1

Reaction catalyzed by iNOS. FAD, flavin adenine dinucleotide; FMN, flavin adenine mononucleotide; NADP, nicotinamide adenine dinucleotide phosphate; HB, tetrahydrobiopterin.

Citation: Bogdan C. 2009. Regulation and Antimicrobial Function of Inducible Nitric Oxide Synthase in Phagocytes, p 367-378. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch22
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Image of FIGURE 2

Overview of the major signaling pathways leading to the induction of iNOS in macrophages. Please note that not all signaling molecules involved are depicted. iNOS-inducing stimuli are surrounded by bold boxes; promoters are shown in gray. AP-1, activated protein-1; GAS, gamma-activated site; IFN, interferon; IKK, inhibitor of nuclear factor κB (IκB) kinase (IKKε is also termed inducible IKK or IKKi); IRAK, IL-1 receptor-associated kinase; IRF, interferon regulatory factor; ISRE, interferon-stimulated response element; JAK, Janus kinase; JNK, c-Jun NH-terminal kinase; NF-κB, nuclear factor κB; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response protein 88; NEMO, NF-κB essential modulator (also termed IKKγ); RIP1, receptor-interacting protein 1; STAT, signal transducer and activator of transcription; TAB1, TAK1-binding protein 1; TAK1, transforming-growth-factor-β-activated kinase; TBK1, TRAF-family-member-associated NF-κB activator (TANK)-binding kinase 1; TLR, toll-like receptor; TNF, tumor necrosis factor; TRADD, TNF receptor-associated death domain; TRAF, tumor necrosis factor receptor-associated factor; TRAM, TRIF-related adaptor molecule, also known as TIR-domain-containing molecule 2 (TICAM2); TRIF, Toll/interleukin 1 receptor (TIR)-domain-containing adaptor protein inducing IFN-β (also known as TIR-domain-containing molecule 1, TICAM1); TYK2, tyrosine kinase 2. In the case of TLR2 and TLR4, a second adaptor protein termed TIRAP (TIR-domain-containing adaptor protein) or MAL (MyD88-adaptor-like protein) is required, which is not shown.

Citation: Bogdan C. 2009. Regulation and Antimicrobial Function of Inducible Nitric Oxide Synthase in Phagocytes, p 367-378. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch22
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Image of FIGURE 3

Mechanisms of the antimicrobial activity of iNOS/NO. For details see text.

Citation: Bogdan C. 2009. Regulation and Antimicrobial Function of Inducible Nitric Oxide Synthase in Phagocytes, p 367-378. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch22
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Image of FIGURE 4

Overview of the arginase pathway and subsequent reactions. For details see text. Mn, manganese cations; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase.

Citation: Bogdan C. 2009. Regulation and Antimicrobial Function of Inducible Nitric Oxide Synthase in Phagocytes, p 367-378. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch22
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Overview of antimicrobial effector mechanisms of phagocytes

Citation: Bogdan C. 2009. Regulation and Antimicrobial Function of Inducible Nitric Oxide Synthase in Phagocytes, p 367-378. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch22

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