Arginase Activity is Inhibited by l -NAME, both In Vitro and In Vivo

Reisser, D; Onier-Cherix, Nathalie; Jeannin, Jean–François

doi:10.1080/1475636021000006252

Cited by 31 publications

(16 citation statements)

References 11 publications

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“…In addition, iNOS inhibitors L-NIL, L-NNA, and L-NAME, which are not transported by CAT-2B failed to recover CD3 expression after T cell stimulation. L-NAME has also been reported to be an ASE inhibitor in vitro and in vivo (33); however, we did not observe an inhibitory effect on ASE activity assay at the concentrations used (data not shown). Stimulation of PM with IL-4 ϩ IL-13 did not induce major changes in the expression of CAT-1 and CAT-2A in PM (data not shown).…”

Section: Discussioncontrasting

confidence: 44%

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Rodríguez

Zea

DeSalvo

et al. 2003

The Journal of Immunology

428

355

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l-Arginine plays a central role in the normal function of several organs including the immune system. It is metabolized in macrophages by inducible nitric oxide synthase to produce nitric oxide, important in the cytotoxic mechanisms, and by arginase I (ASE I) and arginase II (ASE II) to synthesize l-ornithine and urea, the first being the precursor for the production of polyamines needed for cell proliferation. l-Arginine availability can modulate T cell function. Human T cells stimulated and cultured in the absence of l-arginine lose the expression of the TCR ζ-chain (CD3ζ) and have an impaired proliferation and a decreased cytokine production. The aim of this work was to test whether activated macrophages could modulate extracellular levels of l-arginine and alter T cell function, and to determine which metabolic pathway was responsible for this event. The results show that macrophages stimulated with IL-4 + IL-13 up-regulate ASE I and cationic amino acid transporter 2B, causing a rapid reduction of extracellular levels of l-arginine and inducing decreased expression of CD3ζ and diminished proliferation in normal T lymphocytes. Competitive inhibitors of ASE I or the addition of excess l-arginine lead to the re-expression of CD3ζ and recovery of T cell proliferation. In contrast, inducible nitric oxide synthase or ASE II failed to significantly reduce the extracellular levels of l-arginine and modulate CD3ζ expression. These results may provide new insights into the mechanisms leading to T cell dysfunction and the down-regulation of CD3ζ in cancer and chronic infectious diseases.

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Section: Discussioncontrasting

confidence: 44%

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Rodríguez

Zea

DeSalvo

et al. 2003

The Journal of Immunology

428

355

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“…The observation that L-NMMA only inhibited DFMO-mediated vasorelaxation by Ϸ50% can now be easily explained on the basis of emerging literature demonstrating that L-arginine analogues of NOS are also, not surprisingly, potent inhibitors of arginase. 34 In summary, the present findings demonstrate arginase expression in endothelial cells and its role in modulating NOS activity, both biochemically and functionally. With advancing age, expression and function of arginase increases in the vasculature and contributes to endothelial dysfunction.…”

Section: Limitationsmentioning

confidence: 90%

Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels

et al. 2003

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Background-Although abnormal L-arginine NO signaling contributes to endothelial dysfunction in the aging cardiovascular system, the biochemical mechanisms remain controversial. L-arginine, the NO synthase (NOS) precursor, is also a substrate for arginase. We tested the hypotheses that arginase reciprocally regulates NOS by modulating L-arginine bioavailability and that arginase is upregulated in aging vasculature, contributing to depressed endothelial function. Methods and Results-Inhibition of arginase with (S)-(2-boronoethyl)-L-cysteine, HCl (BEC) produced vasodilation in aortic rings from young (Y) adult rats (maximum effect, 46.4Ϯ9.4% at 10 Ϫ5 mol/L, PϽ0.01). Similar vasorelaxation was elicited with the additional arginase inhibitors N-hydroxy-nor-L-arginine (nor-NOHA) and difluoromethylornithine (DFMO). This effect required intact endothelium and was prevented by 1H-oxadiazole quinoxalin-1-one (PϽ0.05 and PϽ0.001, respectively), a soluble guanylyl cyclase inhibitor. DFMO-elicited vasodilation was greater in old (O) compared with Y rat aortic rings (60Ϯ6% versus 39Ϯ6%, PϽ0.05). In addition, BEC restored depressed L-arginine (10 Ϫ4 mol/L)-dependent vasorelaxant responses in O rings to those of Y. Arginase activity and expression were increased in O rings, whereas NOS activity and cyclic GMP levels were decreased. BEC and DFMO suppressed arginase activity and restored NOS activity and cyclic GMP levels in O vessels to those of Y.Conclusions-These findings demonstrate that arginase modulates NOS activity, likely by regulating intracellular L-arginine availability. Arginase upregulation contributes to endothelial dysfunction of aging and may therefore be a therapeutic target.

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“…N(G)-monomethyl-L-arginine can restore the lytic function of PC-infiltrating T cells in vitro (12), but its use in clinic has been discontinued because of severe toxicity (18). In vitro, N(G) nitro-L-arginine methyl ester (L-NAME) causes a significant transcriptional downregulation of endothelial nitric oxide synthase that is overexpressed in endothelial cells associated with PC (19) but can also inhibit Arg activity (20). L-NAME has been reported in several transplantable models to inhibit tumor growth (e.g., ref.…”

Section: Gr1mentioning

confidence: 99%

Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer

Rigamonti

Capuano

Ricupito

et al. 2011

Clinical Cancer Research

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Purpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b þ Gr1þ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity.Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, L-NAME or sildenafil, and evaluated for CD11b þ cells accumulation in the blood, several organs, and the tumor mass and for disease progression.organs and especially in the tumor of the two mouse models. L-NAME and sildenafil impaired the immunosuppressive function of CD11b þ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice. Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance.

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Arginase Activity is Inhibited by l -NAME, both In Vitro and In Vivo

Cited by 31 publications

References 11 publications

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels

Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer

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