Effects of anthrax lethal toxin on human primary keratinocytes

Aims: To investigate the effects of anthrax lethal toxin (LeTx) on human primary keratinocytes. Methods and Results: We show here that human primary keratinocytes are resistant to LeTx-triggered cytotoxicity. All but one of the MEKs (mitogen-activated protein kinase kinases) are cleaved within 3 h, and the cleavage of MEKs in keratinocytes leads to their subsequent proteasome-mediated degradation at different rates. Moreover, LeTx reduced the concentration of several cytokines except RANTES in culture. Conclusions: Our results indicate that primary keratinocytes are resistant to LeTx cytotoxicity, and MEK cleavage does not correlate with LeTx cytotoxicity. Although LeTx is considered as an anti-inflammatory agent, it upregulates RANTES. Significance and Impact of the Study: According to a current view, the action of LeTx results in downregulation of the inflammatory response, as evidenced by diminished expression of several inflammatory biomarkers. Paradoxically, LeTx has been reported to attract neutrophils to cutaneous infection sites. This paper, which shows that RANTES, a chemoattractant for immune cells, is upregulated after exposure of keratinocytes to LeTx, although a number of other markers of the inflammatory response are downregulated. Our results might explain why the exposure of keratinocytes to LeTx results in the recruitment of neutrophils to cutaneous infection sites, while the expression of several inflammatory biomarkers is diminished.