CELLULAR STRESS AND GLUCOCORTICOID HORMONES PROTECT L929 MOUSE FIBROBLASTS FROM TUMOR-NECROSIS-FACTOR-ALPHA CYTOTOXICITY

Adaptive responses to the environment depend on the induction of the ' 'stress response'' in less differentiated organisms and cultured cells and the activation of the hypothalamic-pituitary-adrenal axis in anim als and humans. This indicates that adrenal steroids and stress protei ns play an important role in regulating cell survival in response to n oxious stimuli. In an in vitro model, we analyzed the effects of eithe r dexamethasone (DEX) treatment or environmental changes which can eli cit a stress response, on the survival of cultured L-929 mouse fibrobl asts exposed to the cytotoxic cytokine tumor necrosis factor alpha (TN F-alpha). DEX treatment produced a significant reduction in the apopto tic death of L-929 cells produced by TNF-alpha. Abrogation of the prot ective effect of DEX by actinomycin D and cycloheximide demonstrated t hat protection against TNF-alpha requires de novo synthesis of mRNA an d proteins. The results were similar when L-929 cells were exposed to metabolic (serum starvation) or thermal (heat shock) stresses before T NF-alpha treatment. In both cases the stress process afforded signific ant protection against TNF-alpha cytotoxicity. Inhibition of mRNA and protein synthesis abrogated the protection exerted by stress (serum st arvation) or produced massive death during the stress event (heat shoc k). The similarities in the protective activities of DEX and stress re sponse and the reported interactions between heat shock proteins and g lucocorticoid hormones suggest that stress proteins and glucocorticoid s both belong to an ancient evolutionary pathway which controls cell s urvival.