Heat shock proteins are versatile tools engaged in a variety of cellular functions. Particularly, the stress inducible 70 kDa heat shock protein (hsp70) not only confers protection to cells but also is involved in the regulation of the production of cellular stress response mediators such as cytokines. In addition to cytokines, neurohormones such as the proopiomelanocortin derived αmelanocyte stimulating hormone (αMSH) recently turned out to be potent mediators of inflammatory and immune responses. Thus the present study was performed to investigate the role of αMSH on the expression of hsp70 in a human keratinocyte cell line (HaCaT). The proliferation and differentiation of HaCat cells can be regulated by changing extracellular Ca 2 + concentrations. HaCaT cells induced to differentiate in high Ca 2 + medium (1.5mM) were found to express higher levels of hsp70 protein in comparison to cells grown under low Ca 2 + conditions. Moreover, differentiated HaCaT cells were markedly more restistant to oxidative stress as compared to undifferetiated control cells. αMSH in a dose dependent manner significantly suppressed hsp70 expression in differentiated HaCaT cells, but only had a minor effect on undifferentiated cells. HaCaT cells grown in high Ca 2 + medium upon treatment with αMSH were rendered more sensitive to oxidative stress, which significantly decreased their survival rate. These findings indicate that αMSH which is released by keratinocytes upon injurious stimuli such as tumor promoters or ultraviolet light in an autocrine fashion is able to regulate their cytoprotective protein equipment.