Modulation of cytokine production and protection against lethal endotoxemia by the cardiac glycoside ouabain

Recent studies have shown that cytokines are capable of modulating cardiovascular function and that some drugs used in the treatment of heart failure variably modulate the production of cytokines. To examine whether cardiac glycosides also modulate cytokine production, we evaluated the effects of ouabain on the production of cytokines in vitro and in vivo. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured with or without ouabain in the presence or absence of lipopolysaccharide (LPS). Ouabain induced the production of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in PBMC and induced mRNA of these cytokines, an induction apparently at the transcriptional level. Amiloride, staurosporin, and genistein inhibited cytokine production, and protein kinase C and tyrosine kinase appeared to be involved in the modulation of cytokine production induced by ouabain. However, when PBMC were stimulated with LPS, ouabain suppressed the production of IL-6 and TNF-alpha. To investigate whether ouabain modulates cytokine production in vivo, we evaluated the effects of ouabain in LPS-treated mice. Ouabain was found to protect against LPS-induced lethal toxicity in mice and decreased circulating IL-6 and TNF-alpha levels in vivo. These previously unrecognized immunomodulating effects of a cardiac glycoside may explain either the beneficial or the detrimental effects of these drugs in heart failure patients.