Effect of Ouabain on the Immune System

Ouabain, a known inhibitor of the Na,K-ATPase, has been shown to regulate a number of lymphocyte functions in vitro and in vivo. Lymphocyte proliferation, apoptosis, cytokine production, and monocyte function are all affected by ouabain. The ouabain-binding site occurs at the alpha subunit of the enzyme. The alpha subunit plays a critical role in the transport process, and four different alpha-subunit isoforms have been described with different sensitivities to ouabain. Analysis by RT-PCR indicates that alpha1, alpha2, and alpha3 isoforms are all present in murine lymphoid cells obtained from thymus, lymph nodes, and spleen. In these cells ouabain exerts an effect at concentrations that do not induce plasma membrane depolarization, suggesting a mechanism independent of the classical inhibition of the pump. In other systems, the Na,K-ATPase acts as a signal transducer in addition to being an ion pump, and ouabain is capable of inducing the activation of various signal transduction cascades. Neither resting nor concanavalin A (Con A)-activated thymocytes had their levels of phosphorylated-extracellular signal-regulated kinase (P-ERK) modified by ouabain. However, ouabain decreased p38 phosphorylation induced by Con A in these cells. The pathway induced by ouabain in lymphoid cells is still unclear but might vary with the type and state of activation of the cell.

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“…Ouabain has been proposed to act as a neuroregulator, 19–26 and we now extend its role as an immunomodulator 27 …”

Section: Introductionmentioning

confidence: 78%

Modulation of the Immune System by Ouabain

Rodrigues‐Mascarenhas

Oliveira

Amoêdo

et al. 2009

Annals of the New York Academy of Sciences

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“…Evidence suggests that low concentrations of ouabain can regulate several events in cells belonging to the immune system (Echevarria-Lima and Rumjanek, 2006). Transduction of extracellular signals to intracellular targets is mediated by several protein kinases, including the MAPKs family.…”

Section: Discussionmentioning

confidence: 99%

“…This alternative pathway involves the protein Dlgh1 as an essential scaffold that assembles a module for activation of p38 (Round et al, 2007). Ouabain has been shown to modulate a number of cells from the immune system (Quastel and Kaplan, 1968;Brodie et al, 1995;Marakhova et al, 2005;Echevarria-Lima and Rumjanek, 2006) including thymocytes. Others have found in different cell types that p38 levels can be regulated by ouabain (Li and Wattenberg, 1998;Stathopoulou et al, 2006), probably through inhibition of the Na þ /K þ pump.…”

Section: Introductionmentioning

confidence: 99%

Ouabain inhibits p38 activation in thymocytes

Rodrigues‐Mascarenhas¹,

Bloise²,

Moscat³

et al. 2008

Cell Biology International

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The MAPK p38 is phosphorylated by multiple stimuli and regulates a number of transcription factors. It is reported that activation of p38 leading to the regulation of NFAT may result from an alternative MKK-independent mechanism. This alternative pathway involves the protein Dlgh1 as an essential scaffold that assembles a module for the activation of p38. Ouabain, a specific inhibitor of the Na+/K+-ATPase, is capable of inducing the activation of various signal transduction cascades. In the present work, P-p38 levels of ConA-activated thymocytes treated with ouabain (1, 10 and 100 nM) were measured as also the effect of ouabain on NFATc1 expression. p38 phosphorylation and NFATc1 levels were analyzed by flow cytometry. The results indicated that ouabain inhibited both ConA-dependent increase in P-p38 and NFATc1 levels, which suggests an effect of ouabain on the p38 alternative pathway.

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“…Important actions have also been ascribed to ouabain in the immune system [16] , suggesting that this hormone also works as an immunomodulator. Similar to observations in the CNS, the effects vary with cell type and the concentration used.…”

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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Effect of Ouabain on the Immune System

Cited by 4 publications

References 177 publications

Modulation of the Immune System by Ouabain

Modulation of the Immune System by Ouabain

Ouabain inhibits p38 activation in thymocytes

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

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