Tumor necrosis factor-alpha and interleukin-1 beta synergistically depress human myocardial function

Abstract

TNF-alpha and IL-1beta separately and synergistically depress human myocardial function. Sphingosine likely participates in the TNF-alpha and IL-1beta signal leading to human myocardial functional depression. Therapeutic strategies to reduce production or signaling of either TNF-alpha or IL-1beta may limit myocardial dysfunction in sepsis.

Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

“…The mechanism(s) by which IL-1␤ and TNF-␣ induce contractile dysfunction has also been linked to NO and changes in cellular calcium handling (31). In addition, inhibition of the sphingomyelin signaling pathway abrogated TNF-␣͞IL-1␤-induced myocardial contractile dysfunction (22). Although the present study does not address the role of NO in IL-18-mediated ischemiainduced dysfunction, TNF-␣ depresses the myocardium in a NO-dependant pathway (6).…”

“…We have demonstrated (22) that the presence of exogenous IL-1␤ or TNF-␣ decreases contractile force in human trabeculae in the absence of ischemia. In addition, the combination of these two cytokines have a synergistic effect on the depression of myocardial contractility.…”

“…Therefore, do IL-1␤ and͞or IL-18 trigger the above changes? The addition of IL-1␤ to oxygenated human trabeculae suppresses function (22), and it is known that IL-1␤ induces NOS in cardiac myocytes (23). However, it is not known whether IL-18 acts similarly.…”

“…Although mature IL-1␤ has been shown to directly suppress function when added to human atrial trabeculae (22), it has not been shown whether endogenous IL-1␤ in the heart participates in ischemia-induced dysfunction. In the present study, inhibition of IL-1␤ activity by IL-1 receptor blockade indicates that biologically active endogenous IL-1␤ is present in the heart after ischemia.…”

Acute Reversible Myocardial Depression Associated with Sepsis.

“…TNF-a and IL-ip have similar biological properties and often act synergistically (10) , but clinical studies which have examined the serum levels of these proinflammatory cytokines during septic shock have constantly shown a lack of elevation of serum IL-i p concentration despite a concomitant increased level of 15). These findings suggest that one cannot ascertain whether IL-ip plays a role in the pathogenesis of septic myocardial depression in the clinical setting on the basis of serum IL-lp concentration alone.…”