SUBLETHAL HEAT-SHOCK AND CYCLOSPORINE EXPOSURE PRODUCE TOLERANCE AGAINST SUBSEQUENT CYCLOSPORINE TOXICITY

Sublethal heat shock has been shown to produce tolerance in cells and tissues subsequently exposed to heat or ischemia/ATP depletion. We tes ted whether heating LLC-PK1 cells for 2 h at 42 degrees C induced heat shock protein-70 (HSP-70) gene expression and conferred tolerance aga inst subsequent cyclosporine A (CyA) toxicity. HSP-70 mRNA was increas ed immediately after heat shock, returning to baseline by 4 h. HSP-70 protein increased by 1 h after heat shock and declined thereafter, app roaching baseline after 72 h. Cells heat shocked at 4 and 24 h prior t o CYA exposure were significantly more viable than controls, at CyA co ncentrations near the median lethal dose (LD(50)). Cytoprotection decl ined with time after heat shock, concurrent with declining HSP-70 prot ein levels. Sublethal CyA exposure (50 mu g/ml) for 24 h produced upre gulation of HSP-70 mRNA and protein. Pretreatment with 50 mu g/ml CyA for 24 h followed by exposure to a toxic concentration of CyA (200 mu g/ml) produced significant cytoprotection compared with untreated cont rols. In conclusion, HSP-70 protein induction by sublethal heat shock. or CyA exposure was associated with tolerance against subsequent leth al CyA exposure.