Arginase levels and their association with Th17-related cytokines, soluble adhesion molecules (sICAM-1 and sVCAM-1) and hemolysis markers among steady-state sickle cell anemia patients

Vilas-Boas, Wendell; Cerqueira, Bruno A. V.; Zanette, Angela Maria Dias; Reis, Mitermayer Galvão dos; Barral‐Netto, Manoel; Gonçalves, Marilda Souza

doi:10.1007/s00277-010-0954-9

Cited by 41 publications

(35 citation statements)

References 26 publications

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“…Oxidative stress is also associated with exacerbation of chronic inflammation in SCA patients and vaso‐occlusive events. The present study demonstrated significantly elevated TNF‐α and MPO levels in SCA neutrophils when compared to SCAHU and untreated neutrophils, corroborating numerous studies reporting that patients with SCA, even those with stable disease, have elevated pro‐inflammatory cytokines levels and MPO activity and that treatment with HU is able to reverse this condition .…”

Section: Discussionsupporting

confidence: 90%

The Effect of a Selective Inhibitor of Phosphodiesterase‐9 on Oxidative Stress, Inflammation and Cytotoxicity in Neutrophils from Patients with Sickle Cell Anaemia

Barbosa

Santos

Pedrosa

et al. 2015

Basic Clin Pharma Tox

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The aim of the study was to investigate the possible anti-inflammatory and antioxidant effects of BAY 73-6691 on neutrophils from SCA patients. This study included 35 patients with a molecular diagnosis of SCA, whose neutrophils were isolated and treated with BAY 73-6691 at the concentrations 100, 10, 1.0 and 0.1 lg/mL. LDH release and MTT assays were performed to verify cell viability. To evaluate oxidative stress, the following parameters were determined by spectrophotometric assays: NO and malondialdehyde (MDA) levels and activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). As inflammatory markers, myeloperoxidase (MPO) levels were evaluated by colorimetric assay and TNF-a by enzyme immunoassay. The results showed that neutrophils from SCA patients not treated with hydroxyurea (HU) had significantly lower NO levels and catalase and SOD activity, as well as significantly higher MDA, MPO and TNF-a levels when compared with neutrophils from SCA patients treated with HU and neutrophils from control group. Treatment of SCA neutrophils with BAY 73-6691 resulted in 94%, 200% and 168% increase in NOx levels, SOD and catalase activity, respectively. In addition, there was a reduction of approximately 46% and 45% in TNF-a and MPO levels, respectively. In SCAHU neutrophils, there was a 30% and 44% increase in NOx levels and SOD activity, respectively, and a 28% and 37% decrease in TNF-a and MPO levels, respectively. However, these effects were observed at cytotoxic doses only. The results of this study are original and demonstrate that inhibition of phosphodiesterase-9 in neutrophils from SCA patients with BAY 73-6691 was able to increase the NO bioavailability and attenuate oxidative stress and inflammation in neutrophils from patients not treated with HU.Sickle cell anaemia (SCA) is an inherited disease that results from a single mutation in the b-globin gene, leading to the production of unstable haemoglobin S (HbS) [1]. The haemoglobin polymerizes when deoxygenated and alters the normal biconcave-shaped erythrocyte to a sickle-shaped, unstable and rigid cell with a high expression of adhesion molecules [2]. Thus, SCA is characterized by intravascular haemolysis, chronic inflammation, vaso-occlusive events, endothelial damage and oxidative stress, which culminate in progressive microvascular damage in all organs [3][4][5].Leucocytes are now thought to play a fundamental role in the vaso-occlusive process, adhering to the endothelium and participating in reactive oxygen species (ROS) formation and inflammatory processes in the vasculature [6]. In addition, leucocytosis has been described as a risk factor for sickle crisis, stroke, silent cerebral infarction, acute chest syndrome and disease-related mortality [6][7][8]. Previous studies reported that in SCA individuals, leucocytes appear to exist in a chronic activated state in circulation, even in the basal state, and this activation causes the production of ROS in a NADPH oxidase-mediated respiratory burst [9,10].The reduced bi...

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Section: Discussionsupporting

confidence: 90%

The Effect of a Selective Inhibitor of Phosphodiesterase‐9 on Oxidative Stress, Inflammation and Cytotoxicity in Neutrophils from Patients with Sickle Cell Anaemia

Barbosa

Santos

Pedrosa

et al. 2015

Basic Clin Pharma Tox

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“…Since cytokines have been shown to regulate arginase‐1 expression , we postulated that specific cytokine(s) released by TCR‐activated T cells, but not by T cells activated by other mechanisms, induced arginase‐1 expression in MDSC. As shown in Table , assaying medium collected from activated T‐cell cultures found that TCR‐activated T cells produced more types and higher levels of cytokines than T cells activated by ConA, PMA plus ionomycin, or IL‐2.…”

Section: Resultsmentioning

confidence: 99%

Arginase‐1 is neither constitutively expressed in nor required for myeloid‐derived suppressor cell‐mediated inhibition of T‐cell proliferation

et al. 2018

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Although previous reports suggest that tumor-induced myeloid-derived suppressor cells (MDSC) inhibit T cells by L-arginine depletion through arginase-1 activity, we herein show that arginase-1 is neither inherently expressed in MDSC nor required for MDSC-mediated inhibition. Employing Percoll density gradients, large expansions of MDSC in the bone marrow of tumor-bearing mice were isolated and demonstrated potent inhibition in T-cell proliferation activated by TCR-ligation, Concanavalin A, PMA plus ionomycin, or IL-2. Despite demonstrating characteristic immunosuppressive capacity, these MDSC exhibit no arginase-1 expression and/or exert their inhibitory effects independent of arginase-1 activity. However, arginase-1 expression in MDSC can be induced by exposure to TCR-activated T cells or their culture medium, but not T cells activated by other means or growing tumor cells. Further investigation reveals multiple cytokines secreted by TCR-activated T cells as orchestrating two signaling-relay axes, IL-6-to-IL-4 and GM-CSF/IL-4-to-IL-10, leading to arginase-1 expression in MDSC. Specifically, IL-6 signaling increases IL-4R, enabling IL-4 to induce arginase-1 expression; similarly, GM-CSF in concert with IL-4 induces IL-10R, allowing IL-10-mediated induction. Surprisingly, our study indicates that induction of arginase-1 expression is not conducive to the critical MDSC-mediated inhibition toward T cells, which is rather dependent on direct cell contacts undiminished by PD-L1 blockade or SIRPα deficiency.

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“…A deficiency of L ‐arginine interrupts the electron flow through the eNOS domains and favors the generation of superoxide over NO (25). In some SCD patients, L ‐arginine levels are significantly decreased (22), coinciding with an almost twofold increase in arginase levels (18, 22, 27), resulting in a significant decrease in NO bioavailability. The important role of L ‐arginine in NO production has been demonstrated with the supplementation of L ‐arginine in the diet of both mice and humans.…”

Section: Generation Of Ros In Scdmentioning

confidence: 99%

Role of oxidative stress in the pathogenesis of sickle cell disease

2011

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SummarySickle cell disease (SCD) is a class of hemoglobinopathy in humans, which causes a disruption of the normal activities in different systems. Although this disease begins with the polymerization of red blood cells during its deoxygenating phase, it can erupt into a cascade of debilitating conditions such as ischemiareperfusion injury, inflammation, and painful vaso-occlusion crises. The purpose of this review is to discuss how these phenomena can result in the formation of oxidative stress as well as limit nitric oxide (NO) bioavailability and decrease antioxidant status. The cumulative effects of these traits cause an increase in other forms of reactive oxygen species (ROS), which in turn intensify the symptoms of SCD and generate a vicious circle. Finally, we will discuss antioxidant therapeutic strategies that limit ROS generation and subsequently increase NO bioavailability with respect to endothelial protection in SCD.

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Arginase levels and their association with Th17-related cytokines, soluble adhesion molecules (sICAM-1 and sVCAM-1) and hemolysis markers among steady-state sickle cell anemia patients

Cited by 41 publications

References 26 publications

The Effect of a Selective Inhibitor of Phosphodiesterase‐9 on Oxidative Stress, Inflammation and Cytotoxicity in Neutrophils from Patients with Sickle Cell Anaemia

The Effect of a Selective Inhibitor of Phosphodiesterase‐9 on Oxidative Stress, Inflammation and Cytotoxicity in Neutrophils from Patients with Sickle Cell Anaemia

Arginase‐1 is neither constitutively expressed in nor required for myeloid‐derived suppressor cell‐mediated inhibition of T‐cell proliferation

Role of oxidative stress in the pathogenesis of sickle cell disease

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