Effect of interferon, interleukin-2 and tumor necrosis factor on myocardial cell viability and doxorubicin cardiotoxicity in vitro

Neonatal rat heart myocytes were cultured in plastic 24-well plates for 6 days over which time ATP and protein levels steadily increased. Synchronous beating rates of 40-50 per min are obtained 3 days after plating 1.14 × 10⁶ myocytes/well. The addition of rat interferon (IFN) or recombinant human interleukin (IL-2) or tumor necrosis factor (TNF) at concentrations of 10-1000 U/ml for 24-48 h did not reduce ATP/protein ratios or significantly affect beating rates. A 6-h exposure to doxorubicin concentrations of 0.5 μg/ml and 1.0 μg/ml reduced control ATP/protein ratios of 6.8-7.3 ng/gmg by 78% and 40%, respectively. Importantly, the addition of 100 U/ml of IL-2, TNF or IFN to these doxorubicin concentrations did not alter doxorubicin-induced cardiotoxicity. These results suggest that IL-2, TNF and IFN do not cause direct myocardial cell damage and may be cautiously combined with doxorubicin without enhanced cardiotoxic effects. The reported cardiotoxicity from such cytokines may be principally due to peripheral vascular effects which reflexly stress the heart.