Cyclosporin A induces an atypical heat shock response

Cyclosporin A is a widely used immunosuppressive drug having toxic side effects, in particular on kidneys and liver, as a result of its action on different molecular targets. Here we demonstrate that low doses of CsA are able to induce the expression of the heat shock protein HSP27 and its hyperphosphorylation. It also activates the two heat shock transcription factors, HSF1 and HSF2. Since these factors have been shown to be activated by proteasome inhibition, we tested the hypothesis that the inhibitory action of CsA on the proteasome might be responsible for the activation of HSFs and the subsequent expression of HSP27. The increase in multiubiquitinated proteins as well as the stabilization of p53 following CsA addition argues in favor of this hypothesis. The kidney BSC-1 cells are highly responsive to the addition of CsA: the possible link between HSP27 induction and hyperphosphorylation and nephrotoxicity is discussed.