MODULATION OF CYTOKINE PRODUCTION AND PROTECTION AGAINST LETHAL ENDOTOXEMIA BY THE CARDIAC GLYCOSIDE OUABAIN

Background Recent studies have shown that cytokines are capable of mod ulating cardiovascular function and that some drugs used in the treatm ent 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. Methods and Results Human peripheral blood mononuc lear cells (PBMC) were obtained from healthy volunteers. PBMC were cul tured with or without ouabain in the presence or absence of lipopolysa ccharide (LPS). Ouabain induced the production of interleukin (IL)-1 b eta, IL-6, and tumor necrosis factor (TNF)-alpha in PBMC and induced m RNA of these cytokines, an induction apparently at the transcriptional level. Amiloride, staurosporin, and genistein inhibited cytokine prod uction, and protein kinase C and tyrosine kinase appeared to be involv ed in the modulation of cytokine production induced by ouabain. Howeve r, when PBMC were stimulated with LPS, ouabain suppressed the producti on of IL-6 and TNF-alpha. To investigate whether ouabain modulates cyt okine production in vivo, we evaluated the effects of ouabain in LPS-t reated mice. Ouabain was found to protect against LPS-induced lethal t oxicity in mice and decreased circulating IL-6 and TNF-alpha levels in vivo. Conclusions These previously unrecognized immunomodulating effe cts of a cardiac glycoside may explain either the beneficial or the de trimental effects of these drugs in heart failure patients.