Effect of Ouabain on the Immune System

Abstract

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.

Modulation of the Immune System by Ouabain

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

Ouabain inhibits p38 activation in thymocytes

“…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.…”

“…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.…”

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

“…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.…”