Regulation of Inducible Nitric Oxide Synthase Expression by Macrophage Purinoreceptors and Calcium

Denlinger, Loren C.; Fisette, Philip L.; Garis, Kristen A.; Kwon, Guim; Vázquez‐Torres, Andrés; Simon, Andrew D.; Nguyen, Brenda; Proctor, Richard A.; Bertics, Paul J.; Corbett, John A.

doi:10.1074/jbc.271.1.337

Cited by 161 publications

(120 citation statements)

References 31 publications

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“…Activation of the c-Jun N-terminal kinase cascade and production of IL-1␤ in response to endotoxin have also been observed in this particular macrophage line (33) (R. D. Beigi, S. B. Kertesy, and G. R. Dubyak, unpublished observations). Most experiments and results described below were replicated using RAW 264.7 macrophages, another murine cell line widely used for studies of endotoxin signaling (6,7,(17)(18)(19)34).…”

Section: Endotoxin Signaling In Bac12f5 Macrophagesmentioning

confidence: 99%

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Endotoxin Activation of Macrophages Does Not Induce ATP Release and Autocrine Stimulation of P2 Nucleotide Receptors

Beigi

Dubyak

2000

The Journal of Immunology

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Receptors for extracellular nucleotides (P2, or purinergic receptors) have previously been implicated in the transduction of endotoxin signaling in macrophages. The most compelling evidence has been the observation that inhibitors of ionotropic nucleotide (P2X) receptors, including periodate-oxidized ATP (oATP), attenuate a subset of endotoxin-induced effects such as activation of NF-κB and up-regulation of inducible NO synthase. We investigated whether endotoxin induces ATP release from a murine macrophage cell line (BAC1.2F5) using sensitive on-line assays for extracellular ATP. These cells constitutively released ATP, producing steady-state extracellular concentrations of ∼1 nM when assayed as monolayers of 106 adherent cells bathed in 1 ml of medium. However, the macrophages did not release additional ATP during either acute or prolonged endotoxin stimulation. In addition, cellular ecto-ATPase activities were measured following prolonged endotoxin activation and were found not to be significantly altered. Although oATP treatment significantly attenuated the endotoxin-induced production of NO, this inhibitory effect was not reproduced when the cells were coincubated with apyrase, a highly effective ATP scavenger. These results indicate that activation of macrophages by endotoxin does not induce autocrine stimulation of P2 nucleotide receptors by endogenous ATP released to extracellular compartments. Moreover, the data suggest that the ability of oATP to interfere with endotoxin signaling is due to its interaction with molecular species other than ATP-binding P2 receptors.

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Section: Endotoxin Signaling In Bac12f5 Macrophagesmentioning

confidence: 99%

“…In further support of this model, macrophages are known to express both G protein-coupled (P2Y) and ionotropic (P2X) nucleotide receptors, including the P2X7 pore-forming receptor (12)(13)(14). Additionally, a subset of macrophage responses to endotoxin is modulated by costimulation with exogenous nucleotides (5,(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 96%

Endotoxin Activation of Macrophages Does Not Induce ATP Release and Autocrine Stimulation of P2 Nucleotide Receptors

Beigi

Dubyak

2000

The Journal of Immunology

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“…Nucleosides, and particularly adenosine, can inhibit TNF-␣ and NO synthesis in LPS-stimulated and IFN-␥-induced macrophages (7)(8)(9)(10)(11)(12)19) by mechanisms that rely, at least partially, upon the interaction of adenosine with membrane receptors. The long term control of these regulatory interactions appears to involve receptor synthesis and insertion into the plasma membrane of the activated macrophage, as suggested by evidence that IFN-␥ can up-regulate the synthesis of adenosine receptors of the A2B type (20).…”

Section: ; This Study)mentioning

confidence: 99%

“…Macrophage activation and apoptosis appear to be modulated by extracellular nucleosides and nucleotides (7)(8)(9)(10)(11)(12). These effects are partially explained by their interaction with adenosine and P2 receptors, respectively.…”

mentioning

confidence: 99%

Lipopolysaccharide-induced Apoptosis of Macrophages Determines the Up-regulation of Concentrative Nucleoside Transporters Cnt1 and Cnt2 through Tumor Necrosis Factor-α-dependent and -independent Mechanisms

Soler¹,

Valdés²,

García-Manteiga³

et al. 2001

Journal of Biological Chemistry

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In murine bone marrow macrophages, lipopolysaccharide (LPS) induces apoptosis through the autocrine production of tumor necrosis factor-␣ (TNF-␣), as demonstrated by the fact that macrophages from TNF-␣ receptor I knock-out mice did not undergo early apoptosis. In these conditions LPS up-regulated the two concentrative high affinity nucleoside transporters here shown to be expressed in murine bone marrow macrophages, concentrative nucleoside transporter (CNT) 1 and 2, in a rapid manner that is nevertheless consistent with the de novo synthesis of carrier proteins. This effect was not dependent on the presence of macrophage colony-stimulating factor, although LPS blocked the macrophage colony-stimulating factor-mediated up-regulation of the equilibrative nucleoside transport system es. TNF-␣ mimicked the regulatory response of nucleoside transporters triggered by LPS, but macrophages isolated from TNF-␣ receptor I knock-out mice similarly up-regulated nucleoside transport after LPS treatment. Although NO is produced by macrophages after LPS treatment, NO is not involved in these regulatory responses because LPS up-regulated CNT1 and CNT2 transport activity and expression in macrophages from inducible nitric oxide synthase and cationic amino acid transporter (CAT) 2 knock-out mice, both of which lack inducible nitric oxide synthesis. These data indicate that the early proapoptotic responses of macrophages, involving the up-regulation of CNT transporters, follow redundant regulatory pathways in which TNF-␣-dependent-and -independent mechanisms are involved. These observations also support a role for CNT transporters in determining extracellular nucleoside availability and modulating macrophage apoptosis.

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“…Because Ca 2ϩ regulates several phagocyte antimicrobial responses including generation of reactive oxygen species (33) and reactive nitrogen intermediates (34,35), granule secretion (36), synthesis of cytokines (37), and, in certain cases, phagosome-lysosome (P-L) fusion (9), the Ca 2ϩ -dependence of ATP e -induced killing of M. tuberculosis may be due to multiple effects. We tested the hypothesis that increases in [Ca 2ϩ ] c promote ATP e -induced killing of M. tuberculosis via enhancement of P-L fusion based on the following rationale: 1) During initial infection of naive human M by M. tuberculosis, mycobacterial inhibition of M Ca 2ϩ signaling is tightly coupled to inhibition of P-L fusion and promotion of intracellular bacterial viability (9); 2) pharmacologic reversal of M. tuberculosis-induced inhibition of M Ca 2ϩ signaling results in increased levels of both P-L fusion and mycobacterial killing (9); and 3) ATP e -stimulated killing of BCG does not involve reactive oxygen or reactive nitrogen intermediates species and has not been linked to synthesis or secretion of inflammatory mediators by infected M (8).…”

Section: Atp Induces Ca 2ϩ -Dependent Maturation Of M Tuberculosis Pmentioning

confidence: 99%

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

Kusner

Barton²

2001

The Journal of Immunology

140

114

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Advances in therapy for tuberculosis will require greater understanding of the molecular mechanisms of pathogenesis and the human immune response in this disease. Exposure of Mycobacterium tuberculosis-infected human macrophages to extracellular ATP (ATPe) results in bacterial killing, but the molecular mechanisms remain incompletely characterized. In this study, we demonstrate that ATPe-induced bactericidal activity toward virulent M. tuberculosis requires an increase in cytosolic Ca2+ in infected macrophages. Based on our previous work with primary infection of human macrophages, we hypothesized that the Ca2+ dependence of ATP-induced killing of intracellular M. tuberculosis was linked to promotion of phagosome-lysosome fusion. Using confocal laser-scanning microscopy, we demonstrate that ATPe induces fusion of the M. tuberculosis-containing phagosome with lysosomes, defined by accumulation of three lysosomal proteins and an acidophilic dye. Stimulation of phagosome-lysosome fusion by ATPe exhibited distinct requirements for both Ca2+ and phospholipase D and was highly correlated with killing of intracellular bacilli. Thus, key signal transduction pathways are conserved between two distinct models of human macrophage antituberculous activity: primary infection of naive macrophages and physiologic stimulation of macrophages stably infected with M. tuberculosis.

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Regulation of Inducible Nitric Oxide Synthase Expression by Macrophage Purinoreceptors and Calcium

Cited by 161 publications

References 31 publications

Endotoxin Activation of Macrophages Does Not Induce ATP Release and Autocrine Stimulation of P2 Nucleotide Receptors

Endotoxin Activation of Macrophages Does Not Induce ATP Release and Autocrine Stimulation of P2 Nucleotide Receptors

Lipopolysaccharide-induced Apoptosis of Macrophages Determines the Up-regulation of Concentrative Nucleoside Transporters Cnt1 and Cnt2 through Tumor Necrosis Factor-α-dependent and -independent Mechanisms

ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

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