Ouabain exacerbates activation-induced cell death in human peripheral blood lymphocytes

Esteves, Mabel Barbosa; Marques‐Santos, Luis Fernando; Affonso-Mitidieri, O. R.; Rumjanek, Vivian M.

doi:10.1590/s0001-37652005000200008

Cited by 17 publications

(10 citation statements)

References 37 publications

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“…This is in accordance with the cell death observed in the thymus and the activation of an apoptotic pathway. Furthermore, other authors have demonstrated that OUA enhances apoptosis of different cells, including peripheral blood lymphocytes (Esteves et al 2005), cortical neurons (Xiao et al 2002) and telencephalic cells (Brines and Robbins 1992).…”

Section: Discussionmentioning

confidence: 96%

Synergistic Effect Between Ouabain and Glucocorticoids for the Induction of Thymic Atrophy

Rodrigues‐Mascarenhas

Santos

Rumjanek

2006

Bioscience Reports

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The present report shows that thymocyte death, induced by glucocorticoids, may be modulated in vivo by ouabain. Young, ten days old, mice injected with 140 mg/kg sodium succcinate of hydrocortisone (HC) intraperitonially (i.p.) displayed, 24 h after the injection, a decrease in thymus size and cellular content, an effect that was magnified when ouabain (OUA) 0.56 mg/kg, i.p. was given 1 h prior to the HC injection. Ouabain per se was not capable of producing these changes. Both HC and the combination OUA plus HC induced the death of immature double positive lymphocytes (CD4+CD8+) whereas CD69+ cells survived both treatments. An increase in annexin positive cells and a decrease in mitochondrial membrane potential, assessed by cytofluorimetry, using the fluorescent dye DiOC6, was observed in thymocytes from HC treated animals indicating apoptosis of these cells. Furthermore, a synergistic effect between OUA and HC was also observed using this parameter. The synergy observed in the thymus of animals treated with glucocorticoids and OUA might occur under stress, when both hormones are released, or in situations when ouabain is administered exogenously in a moment of the circadian cycle when glucocorticoid levels are elevated. However the impact of this effect on the immune response is still unknown.

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Section: Discussionmentioning

confidence: 96%

Synergistic Effect Between Ouabain and Glucocorticoids for the Induction of Thymic Atrophy

Rodrigues‐Mascarenhas

Santos

Rumjanek

2006

Bioscience Reports

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“…Similar to observations in the CNS, the effects vary with cell type and the concentration used. Ouabain was shown to inhibit mitogen-induced lymphocyte proliferation [17] , to regulate the production of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor-␣ [18,19] , to enhance lipopolysaccharide-induced nitric oxide production [20] and to induce mitogen-activated cell apoptosis [21,22] . Furthermore, nanomolar concentrations of ouabain led to an increase in intracellular Ca 2+ as a result of mobilization of both intracellular and extracellular Ca 2+ pools [23], and this was shown to correlate with the expression of CD69, a tyrosine kinase related to cell activation [24] .…”

mentioning

confidence: 99%

mCD14 Expression in Human Monocytes Is Downregulated by Ouabain via Transactivation of Epithelial Growth Factor Receptor and Activation of p38 Mitogen-Activated Protein Kinase

Valente¹,

Nascimento

Araújo

et al. 2009

Neuroimmunomodulation

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Background and Aims: The steroid ouabain is found in plasma and in many mammalian tissues, and is now considered as a hormone. In the immune system, ouabain regulates a number of lymphocyte functions, but little is known about its effects on monocyte function. Monocytes are important for adequate immune responses. The aim of this work was to analyze the effect of ouabain on mCD14 expression, a surface molecule involved in the response against Gram-negative bacteria and phagocytosis. Methods: Human peripheral blood mononuclear cells obtained from healthy donors were separated by density gradient centrifugation. Monocytes were separated by adherence and treated for 24 h with 100 nM ouabain. mCD14, CD1a and P-p38 expression was analyzed by flow cytometry. Inhibitors of cell-signaling pathways, i.e. SB202190, reduced glutathione, rottlerin, tyrphostin A23, genistein, chelerythrine chloride, PD98059, PP1 and Ly 294002, were used concomitantly with ouabain to observe their effect on mCD14 expression. Results: Ouabain induced a significant decrease in mCD14 expression. This feature was not related to receptor endocytosis or cell death. Furthermore, mCD14 downregulation did not reflect a shift in differentiation into dendritic cells because this hormone failed to induce CD1a expression. Amongst several inhibitors of cell-signaling pathways triggered by ouabain, only epidermal growth factor receptor (EGFR) and p38 mitogen-activated protein kinase (MAPK) inhibitors (tyrphostin A23 and SB202109) significantly reverted the effect of ouabain on mCD14 expression. Accordingly, the levels of P-p38 were increased on monocytes after ouabain treatment. However, incubation with epidermal growth factor did not alter mCD14 expression. Conclusion: These findings suggest that ouabain downregulates mCD14 expression on monocytes through EGFR transactivation and p38 MAPK activation.

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“…A different view is put forward by other authors [191,192], according to them loss of cytosolic K + occurs downstream of mitochondrial depolarization and caspase activation, but they also consider this step crucial for the activation of endonucleases [192,193]. In our experience the loss of mitochondrial membrane potential was clearly evident only when PHA-activated cells were exposed to ouabain and appeared to be a late event [181].…”

Section: Effect Of Ouabain On Activation-induced Cell Death (Aicd)mentioning

confidence: 46%

“…Fas and FasL are expressed in PHA-activated lymphocytes exposed or not to ouabain, and we observed that the induction of the apoptotic process using anti-Fas as an agonist, led to an increased amount of apoptotic cells in PHA-activated cultures in the presence of ouabain [181]. In the T cell line Jurkat, ouabain potentiates Fas-induced apoptosis and the death program triggered by this molecule [182,183].…”

Section: Effect Of Ouabain On Activation-induced Cell Death (Aicd)mentioning

confidence: 97%

Effect of Ouabain on the Immune System

Echevarria-Lima¹,

Rumjanek

2006

CHYR

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Immune dysfunction has been reported in patients with hypertension and in spontaneously hypertensive rats. Increased circulating levels of ouabain were observed in experimental models and in human hypertension. Despite the correlation between immunologic depression and hypertension, the mechanisms involved are unclear. This review examines evidences of immune dysfunction in hypertension and presents observations suggesting that ouabain is capable of inducing lymphocyte changes related to some of the immune disturbances observed. Defects in thymocytes, mature lymphocyte subsets, lymphocyte proliferation, cytokines balance and increased immunoglobulin production, were reported in animal models and/or hypertensive patients. Ouabain potentiates the effects of glucocorticoids on thymocytes, inducing plasma membrane depolarization, loss of mitochondrial membrane potential, changes in CD69 levels, increased intracellular calcium and apoptosis of thymocyte subsets. The activation of mature lymphocytes is inhibited by ouabain following different stimuli and these cells display changes in c-myc, CD69 and CD25 levels, plasma membrane polarization and mitochondrial membrane potential. These cells underwent apoptosis, suggesting an exacerbation of the process of activation induced cell death. Levels of cytokines such as IL-1, IL-2, IL-6, TNF, and GM-CSF are modified by ouabain. Some of the ouabain effects may result from a mechanism different from the traditional inhibition of the Na + /K + ATPase.

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Ouabain exacerbates activation-induced cell death in human peripheral blood lymphocytes

Cited by 17 publications

References 37 publications

Synergistic Effect Between Ouabain and Glucocorticoids for the Induction of Thymic Atrophy

Synergistic Effect Between Ouabain and Glucocorticoids for the Induction of Thymic Atrophy

mCD14 Expression in Human Monocytes Is Downregulated by Ouabain via Transactivation of Epithelial Growth Factor Receptor and Activation of p38 Mitogen-Activated Protein Kinase

Effect of Ouabain on the Immune System

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