Regulation of arginase isoforms I and II by IL-4 in cultured murine peritoneal macrophages

Louis, Claudine A.; Mody, V.; Henry, William P.; Reichner, Jonathan S.; Albina, Jorge E.

doi:10.1152/ajpregu.1999.276.1.r237

Cited by 72 publications

(82 citation statements)

References 34 publications

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“…First, arginase up-regulation might rely on systemic inflammation and increased proinflammatory cytokines. Indeed, previous data demonstrated that arginase expression in cultured endothelial cells can be regulated by various proinflammatory cytokines or by lipopolysaccharide (41)(42)(43). In our study, in accordance with a systemic state of inflammation in AIA rats 21 days after the onset of arthritis, plasma levels of IL-6 increased by 62% in AIA rats compared with controls.…”

Section: Discussionsupporting

confidence: 88%

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether arginase pathway abnormalities occur in vessels from rats with adjuvant-induced arthritis (AIA), and to determine whether the up-regulation of arginase, which reciprocally regulates nitric oxide synthase (NOS) by competing for the same substrate, L-arginine, contributes to endothelial dysfunction in AIA.Methods. We performed vascular reactivity experiments on thoracic aortic rings from AIA rats and control rats, and we investigated the response of rings to norepinephrine (NE), sodium nitroprusside (SNP), and acetylcholine (ACh). ACh-induced relaxation was evaluated in the presence (or not in the presence) of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), the arginase inhibitor N -hydroxy-nor-Larginine (nor-NOHA), or both. Aortic arginase activity was measured using a spectrophotometric method, and the expression of arginase and endothelial NOS (eNOS) was evaluated by Western blotting.Results. ACh-induced vasodilation was significantly impaired in AIA rats, while the responses to NE and to SNP did not differ from those in control rats. L-NAME reduced ACh-induced vasodilation to a lesser extent in AIA rats than in control rats. Incubation of aortic rings with nor-NOHA enhanced the vascular response to ACh in AIA rats and reversed the effects of L-NAME. Compared with control rats, AIA rats exhibited increased vascular expression of arginase II (by 22%) (P < 0.05) as well as increased arginase activity (by 49%) (P < 0.05), whereas eNOS expression was unchanged. Finally, arginase activity and expression correlated positively with arthritis severity.Conclusion. Our results are consistent with the notion that arginase up-regulation plays a role in AIAassociated endothelial dysfunction. They suggest that arginase might be an attractive new target for treating endothelial dysfunction in arthritis.

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Section: Discussionsupporting

confidence: 88%

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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“…Whereas CAT-1, CAT-2B, and CAT-3 are high affinity (K M 100 mol/L) transporters for L-arginine, CAT-2A is an alternatively spliced variant of CAT-2B that possesses low affinity for L-arginine (K M 1 to 2 mmol/L) (32). In accordance with Louis et al (10), our data show that PM stimulated with IL-4 ϩ IL-13 up-regulate the expression of CAT-2B, displaying a similar kinetics to ASE I (Figs. 1C and 6B).…”

Section: Discussionsupporting

confidence: 79%

“…Stimulation of murine macrophages with IFN-␥ up-regulates iNOS exclusively, whereas IL-4, IL-10 and IL-13 induce ASE I (8,9). The mitochondrial isoform ASE II is not significantly modulated by Th1 or Th2 cytokines (7,10). …”

mentioning

confidence: 99%

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

Rodríguez

Zea

DeSalvo

et al. 2003

The Journal of Immunology

425

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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“…Our previous study supports this contention, because inhibition of arginase activity enhances NO production from LPS-activated macrophages (26). Recently, arginase activity has been shown to be up-regulated by endogenous factors such as TGF-␤ (21) and Th-2 cell-derived cytokines IL-4 and IL-10 (22)(23)(24)(25). Interestingly, these factors were also reported to suppress NO production (21,22,41), implying that arginase might be an intrinsic modulator of NO production.…”

Section: Discussionsupporting

confidence: 69%

The Involvement of Tyrosine Kinases, Cyclic AMP/Protein Kinase A, and p38 Mitogen-Activated Protein Kinase in IL-13-Mediated Arginase I Induction in Macrophages: Its Implications in IL-13-Inhibited Nitric Oxide Production

Chang

Zoghi

Liao

et al. 2000

The Journal of Immunology

104

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In macrophages, l-arginine can be used by NO synthase and arginase to form NO and urea, respectively. Therefore, activation of arginase may be an effective mechanism for regulating NO production in macrophages through substrate competition. Here, we examined whether IL-13 up-regulates arginase and thus reduces NO production from LPS-activated macrophages. The signaling molecules involved in IL-13-induced arginase activation were also determined. Results showed that IL-13 increased arginase activity through de novo synthesis of the arginase I mRNA and protein. The activation of arginase was preceded by a transient increase in intracellular cAMP, tyrosine kinase phosphorylation, and p38 mitogen-activated protein kinase (MAPK) activation. Exogenous cAMP also increased arginase activity and enhanced the effect of IL-13 on arginase induction. The induction of arginase was abolished by a protein kinase A (PKA) inhibitor, KT5720, and was down-regulated by tyrosine kinase inhibitors and a p38 MAPK inhibitor, SB203580. However, inhibition of p38 MAPK had no effect on either the IL-13-increased intracellular cAMP or the exogenous cAMP-induced arginase activation, suggesting that p38 MAPK signaling is parallel to the cAMP/PKA pathway. Furthermore, the induction of arginase was insensitive to the protein kinase C and p44/p42 MAPK kinase inhibitors. Finally, IL-13 significantly inhibited NO production from LPS-activated macrophages, and this effect was reversed by an arginase inhibitor, l-norvaline. Together, these data demonstrate for the first time that IL-13 down-regulates NO production through arginase induction via cAMP/PKA, tyrosine kinase, and p38 MAPK signalings and underline the importance of arginase in the immunosuppressive activity of IL-13 in activated macrophages.

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Regulation of arginase isoforms I and II by IL-4 in cultured murine peritoneal macrophages

Cited by 72 publications

References 34 publications

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

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

The Involvement of Tyrosine Kinases, Cyclic AMP/Protein Kinase A, and p38 Mitogen-Activated Protein Kinase in IL-13-Mediated Arginase I Induction in Macrophages: Its Implications in IL-13-Inhibited Nitric Oxide Production

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