TUMOR NECROSIS FACTOR-ALPHA-INDUCED EXPRESSION OF HEAT-SHOCK-PROTEIN-72 IN ADULT FELINE CARDIAC MYOCYTES

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that is elaborated in a myriad of cardiac disease states. Although the biological role for TNF-alpha in the adult heart is not known, a rece nt study in fetal myocardial cells has shown that this cytokine increa ses the synthesis of low-molecular-weight stress proteins. These findi ngs suggested the interesting possibility that TNF-alpha might play a functional role in the adult heart by increasing the expression of str ess proteins in cardiac myocytes. Accordingly, the purpose of this stu dy was to determine whether TNF-alpha would modulate the expression of heat shock protein 72 (HSP 72), a stress protein that is thought to e xert protective effects in the adult heart. Stimulation of adult felin e cardiac myocytes with a range of TNF-alpha concentrations (10-1,000 U/ml) for 12 h showed that concentrations of TNF-alpha less than or eq ual to 10 U/ml had no effect on HSP 72 expression, whereas TNF-alpha c oncentrations greater than or equal to 50 U/ml produced significant in creases in HSP 72 expression. Continuous stimulation of cardiac myocyt es with a single concentration of TNF-alpha (200 U/ml) revealed time-d ependent effects on HSP 72 expression: increased HSP 72 expression was detected 3 h following cytokine stimulation, peaked by similar to 12 h, and then returned toward baseline by 48 h. Additional studies indic ated that stimulation of the type 1 TNF receptor was responsible for t he increase in HSP 72 expression. In summary, these studies constitute the initial demonstration that TNF-alpha exerts concentration- and ti me-dependent effects on the expression of HSP 72 in the adult mammalia n cardiac myocytes, thus suggesting the interesting possibility that t he elaboration of TNF-alpha may enable the heart to better withstand c ertain forms of stress.