Nitric Oxide and Macrophage Function

MacMicking, John D.; Xie, Qiao-wen; Nathan, Carl

doi:10.1146/annurev.immunol.15.1.323

Cited by 3,756 publications

(2,896 citation statements)

References 183 publications

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“…4A and data not shown). We confirmed the effectiveness of these treatments by measuring nitric oxide (NO) release [27][28][29]. As expected, IFN-g alone and IFN-g in combination with TNF-a or LPS induced, while both IL-4 and IL-13 blocked, NO release (Fig.…”

Section: Effects On P2x 4 R By Classical and Alternative Activation Osupporting

confidence: 82%

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Stokes

Surprenant

2009

Eur J Immunol

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ATP-gated P2X 4 receptors (P2X 4 R) in macrophages and microglia have been implicated in neuropathic and inflammatory pain by currently unidentified mechanisms. P2X 4 R are found predominantly in intracellular lysosomal compartments but can be rapidly trafficked to the surface membrane by procedures that induce endolysosomal secretion. We studied total and surface membrane P2X 4 R protein expression by Western blot and biotinylation assays and functional expression by whole-cell patch clamp assays in human and rat alveolar macrophages in response to phagocytosis of zymosan and opsonized zymosan bioparticles and to classical and alternative macrophage activation. Unstimulated macrophages showed high total protein expression but very low functional expression. Phagocytosis rapidly (within 4 h) increased functional P2X 4 R expression by 2-to 7-fold as did chloroquine, an agent known to induce lysosomal secretion. In contrast, classical activation of macrophage for 48 h with IFN-c and TNF-a or IFN-c and LPS reduced surface and functional P2X 4 R expression by 3-fold without altering total P2X 4 R protein levels. Alternative activation with IL-4 or IL-13 did not alter total, surface or functional expression of P2X 4 R. This is the first study of the regulation of P2X 4 R in macrophages by physiological stimuli and presents a picture whereby P2X 4 R become functional in response to initial phagocytic stimuli but return to a non-functional state during sustained activation by classical macrophage activation.Key words: Inflammation . Ion channels . Patch-clamp . Purine receptors Introduction Extracellular ATP acts as a ''danger signal'' when it is released from cells during tissue damage and inflammation; it acts on metabotropic (G-protein coupled) P2Y and ionotropic (cation channel) P2X purinergic receptors to affect several inflammatory and immune responses [1,2]. There are seven members of the P2X receptor family (P2X 1-7 R) that show widespread distribution in both neuronal and non-neuronal tissues [3]. Two of these seven members, P2X 4 R and P2X 7 R, have generated increasing interest as potential anti-inflammatory drug targets [2,4,5]. The case for P2X 7 R is now well established: Stimulation of P2X 7 R in activated monocytes, macrophages and microglia leads to rapid release of pro-inflammatory IL-1b and IL-18 cytokines, to phospholipase D activation and, if stimulation is sustained, to apopotosis [1,[3][4][5]. Classical activation of macrophages, generally induced by IFN-g and/or LPS, up-regulates P2X 7 R mRNA and protein levels and functional expression [6,7] and this correlates well with a role for P2X 7 R in bacterial killing [8,9]. Recently, highly selective and potent P2X 7 R antagonists have been identified [10] with one of these showing initial positive results in Phase II clinical trials for rheumatoid arthritis [11]. The case for P2X 4 R remains tentative, largely due to the absence of selective P2X 4 R antagonists and the complicating presence of P2X 7 R, which is generally co-expressed with P2X 4 R in ...

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Section: Effects On P2x 4 R By Classical and Alternative Activation Osupporting

confidence: 82%

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Stokes

Surprenant

2009

Eur J Immunol

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“…The consequence of this breakdown and the mechanism of inactivation of NO intermediates released from GSNO inside the pathogen remains to be elucidated. Production of the toxic NO as the result of GSNO breakdown seems paradoxical, due to the toxicity of NO [29]. However, bearing in mind the short half life of NO, and our previous studies showing that mycothiol efficiently protects mycobacteria against its bactericidal effect [11], NO is considered much less toxic compared to GSNO [30].…”

Section: Discussionmentioning

confidence: 98%

Glutathione disulfide and S‐nitrosoglutathione detoxification by Mycobacteriumtuberculosis thioredoxin system

et al. 2009

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a b s t r a c tMycobacterium tuberculosis resides within alveolar macrophages. These phagocytes produce reactive nitrogen and oxygen intermediates to combat the invading pathogens. The macrophage glutathione (GSH) pool reduces nitric oxide (NO) to S-nitrosoglutathione (GSNO). Both glutathione disulfide (GSSG) and GSNO possess mycobactericidal activities in vitro. In this study we demonstrate that M. tuberculosis thioredoxin system, comprises of thioredoxin reductase B2 and thioredoxin C reduces the oxidized form of the intracellular mycothiol (MSSM) and is able to efficiently reduce GSSG and GSNO in vitro. Our study suggests that the thioredoxin system provide a general reduction mechanism to cope with oxidative stress associated with the microbe's metabolism as well as to detoxify xenobiotics produced by the host.

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“…In addition to the inhibitory effects on proinflammatory cytokines production, albaconol also significantly attenuated the secretion of NO of macrophages induced by LPS. The small amount of NO produced by constitutive NOS, including endothelial NOS and neural NOS, is an important regulator of physiological homeostasis, whereas the large amount of NO produced by inducible NOS has been closely correlated with the pathophysiology in a variety of diseases and inflammation (21). NO is induced by LPS or immunological stimuli (e.g., IFN-γ) implicating as a mediator of inflammation (22).…”

Section: Discussionmentioning

confidence: 99%

Albaconol, a Plant-Derived Small Molecule, Inhibits Macrophage Function by Suppressing NF-κB Activation and Enhancing SOCS1 Expression

et al. 2008

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Discovery and functional identification of plant-derived small compounds as the immunosuppressant attract much attention these years. Albaconol is a new kind of small compound, prenylated resorcinol, isolated from the fruiting bodies of the inedible mushroom Albatrellus confluens. Our previous studies showed that albaconol can inhibit tumor cell growth and dendritic cell maturation. However, the immunomodulatory roles and the underlying mechanisms of albaconol have not been fully understood. In this study we investigated the effects of albaconol on the proliferation and LPS-induced proinflammatory cytokine production of macrophages. Albaconol, when used at a dose higher than 1.0 μg/ml, inhibited proliferation of RAW264.7 cells in a dose-and time-dependent manner, and could induce cellular apoptosis when used at high dosage (≥ 7.5 μg/ml). Furthermore, we found that albaconol used at a lower dosage without apoptosis induction could significantly inhibit LPS-induced TNF-α, IL-6, IL-1β and NO production in RAW264.

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Nitric Oxide and Macrophage Function

Cited by 3,756 publications

References 183 publications

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Glutathione disulfide and S‐nitrosoglutathione detoxification by Mycobacteriumtuberculosis thioredoxin system

Albaconol, a Plant-Derived Small Molecule, Inhibits Macrophage Function by Suppressing NF-κB Activation and Enhancing SOCS1 Expression

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Nitric Oxide and Macrophage Function

Cited by 3,756 publications

References 183 publications

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

Glutathione disulfide and S‐nitrosoglutathione detoxification by Mycobacteriumtuberculosis thioredoxin system

Albaconol, a Plant-Derived Small Molecule, Inhibits Macrophage Function by Suppressing NF-κB Activation and Enhancing SOCS1 Expression

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Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation

Dynamic regulation of the P2X₄ receptor in alveolar macrophages by phagocytosis and classical activation