Mycobacterium tuberculosis (MTB)- stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB

Rich, Elizabeth A.; Torres, Martha; Sada, Eduardo; Finegan, Candace K.; Hamilton, Beverly D.; Toossi, Zahra

doi:10.1016/s0962-8479(97)90005-8

Cited by 126 publications

(95 citation statements)

References 30 publications

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“…Macrophages, neutrophils, and other fagocyting cells are key antimicrobial components of the immune response, due to the fact that they can generate a large amount of highly toxic molecules as reactive oxygen and nitrogen metabolites, and hydrolytic enzymes such as acid hydroxylase (Chan et al 1992;Clemens and Horwitz 1995;Rich et al 1997). Despite this toxic environment M. tuberculosis can survive thanks to several mechanisms (Pieters, 2008).…”

Section: Thioredoxin System Of Selected Pathogens As a Therapeutic Tamentioning

confidence: 99%

Thioredoxin system – a novel therapeutic target

Koháryová¹,

Kollárová²

2015

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Abstract. Nowadays there are numerous pathogens that have created a resistance to commonly used antibiotics and drugs. Therefore research is focused on finding new therapeutic targets and on determination of their 3D structures that could help in designing new effective substances and inhibitors. Thioredoxin system not only plays a crucial role as thiol/disulfide redox controller, it is also essential for certain organisms as the only system ensuring the redox homeostasis. It is the redox-regulating function, which makes thioredoxin and thioredoxin reductase attractive for scientific research, especially in many studies of diseases caused by redox instability. Thanks to these facts, the proteins of thioredoxin system are suitable candidates for new therapeutic purposes. In this review we summarized the basic features of the thioredoxin system, we justified why the proteins of thioredoxin system are appropriate therapeutical targets and we provided overview of the possibilities of their inhibition by several types of inhibitors.

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Section: Thioredoxin System Of Selected Pathogens As a Therapeutic Tamentioning

confidence: 99%

Thioredoxin system – a novel therapeutic target

Koháryová¹,

Kollárová²

2015

gpb

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“…While murine macrophages produce high levels of NO in response to LPS and IFN-␥, human macrophages are not similarly responsive. However, high levels of NO can be produced by human AM stimulated in vitro with live Mtb (27,36). We stimulated RAW 264.7 cells and primary human AM with Mtb in the presence and the absence of E5531.…”

Section: E5531 Inhibits Lps-and Mtb-induced Tnf-␣ Production But Notmentioning

confidence: 99%

Differential Effects of a Toll-Like Receptor Antagonist on Mycobacterium tuberculosis-Induced Macrophage Responses

Means

Jones

Schromm

et al. 2001

The Journal of Immunology

252

178

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We previously showed that viable Mycobacterium tuberculosis (Mtb) bacilli contain distinct ligands that activate cells via the mammalian Toll-like receptor (TLR) proteins TLR2 and TLR4. We now demonstrate that expression of a dominant negative TLR2 or TLR4 proteins in RAW 264.7 macrophages partially blocked Mtb-induced NF-κB activation. Coexpression of both dominant negative proteins blocked virtually all Mtb-induced NF-κB activation. The role of the TLR4 coreceptor MD-2 was also examined. Unlike LPS, Mtb-induced macrophage activation was not augmented by overexpression of ectopic MD-2. Moreover, cells expressing an LPS-unresponsive MD-2 mutant responded normally to Mtb. We also observed that the lipid A-like antagonist E5531 specifically inhibited TLR4-dependent Mtb-induced cellular responses. E5531 could substantially block LPS- and Mtb-induced TNF-α production in both RAW 264.7 cells and primary human alveolar macrophages (AMφ). E5531 inhibited Mtb-induced AMφ apoptosis in vitro, an effect that was a consequence of the inhibition of TNF-α production by E5531. In contrast, E5531 did not inhibit Mtb-induced NO production in RAW 264.7 cells and AMφ. Mtb-stimulated peritoneal macrophages from TLR2- and TLR4-deficient animals produced similar amounts of NO compared with control animals, demonstrating that these TLR proteins are not required for Mtb-induced NO production. Lastly, we demonstrated that a dominant negative MyD88 mutant could block Mtb-induced activation of the TNF-α promoter, but not the inducible NO synthase promoter, in murine macrophages. Together, these data suggest that Mtb-induced TNF-α production is largely dependent on TLR signaling. In contrast, Mtb-induced NO production may be either TLR independent or mediated by TLR proteins in a MyD88-independent manner.

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“…Genome-wide association studies link NOS2 with an increased incidence of TB (4)(5)(6)(7)(8), although the expression and/or activity of iNOS resulting from these polymorphisms are unknown. Still other investigators reported that iNOS and NO production in TB patients correlates with less severe disease, and NO production by human alveolar MFs ex vivo inhibits mycobacterial growth (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Rapovy¹,

Zhao²,

Bricker³

et al. 2015

The Journal of Immunology

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Microbicidal NO production is reliant on inducible NO synthase–mediated l-arginine metabolism in macrophages (MΦs). However, l-arginine supply can be restricted by arginase activity, resulting in inefficient NO output and inhibition of antimicrobial MΦ function. MΦs circumvent this by converting l-citrulline to l-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine MΦs supplied l-arginine, l-citrulline, or both amino acids. Using liquid chromatography–tandem mass spectrometry, we determined that l-arginine synthesized from l-citrulline was less effective as a substrate for arginase-mediated l-ornithine production compared with l-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette–Guérin infection and costimulation with IFN-γ, we observed that MΦ arginase activity did not inhibit production of NO derived from l-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in l-arginine. Furthermore, we found that arginase-expressing MΦs preferred l-citrulline over l-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of l-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.

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Mycobacterium tuberculosis (MTB)- stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB

Cited by 126 publications

References 30 publications

Thioredoxin system – a novel therapeutic target

Thioredoxin system – a novel therapeutic target

Differential Effects of a Toll-Like Receptor Antagonist on Mycobacterium tuberculosis-Induced Macrophage Responses

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

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