Modulation of the Immune System by Ouabain

Abstract

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.

Death of ouabain-treated renal epithelial cells: evidence for p38 MAPK-mediated Na i + /K i + -independent signaling

“…In contrast, mouse and human macrophages apoptosis triggered by activation of P2X receptors and ROS is mediated by p38 activation [34,35]. Neither survival nor p38 phosphorylation were affected in murine thymocytes subjected to 18 h incubation with 0.1 lM ouabain [19]. These data are consistent with cell-type specific actions of ouabain on p38 phosphorylation and survival demonstrated in this study.…”

“…and ROS in the death of ouabain-treated MDCK cells [16]. Based on these negative results, we focused on the role of mitogen-activated protein kinases (MAPK) whose tissuespecific impact on cell survival has been shown in numerous studies [17][18][19]. Our data demonstrate that the death of ouabain-treated REC is mediated by activation of p38 MAPK via the Na i ?…”

Dynamics of murine B lymphocytes is modulated by in vivo treatment with steroid ouabain

“…Ouabain was also described to have cardiotonic properties presenting hypertensinogenic activity that leads to increased blood pressure (Manunta et al, 2000(Manunta et al, , 2001a. Besides of its cardiotonic role, ouabain also presents activity on the immune system (Rodrigues-Mascarenhas et al, 2009).…”

Involvement of Na+, K+-ATPase and its inhibitors in HuR-mediated cytokine mRNA stabilization in lung epithelial cells

“…In fact, many investigations consider that besides being a cardiotonic substance, ouabain can also act as a potential immunomodulator [11]. For example, ouabain was shown to affect various immunological processes, such as lymphocyte proliferation, apoptosis, and monocyte function [11]. However, the most prominent role of ouabain involved in the immune system is its ability to modulate cytokine production.…”