Effects of mammalian target of rapamycin inhibitors on cytokine production and differentiation in keratinocytes

Risk factors for the development of cutaneous squamous cell carcinoma (c SCC ) include ultraviolet radiation and immunosuppression. In particular, solid organ transplant recipients show a high incidence of c SCC , depending on the immunosuppressive regimen. While azathioprine or calcineurin inhibitors increase the risk of c SCC development, mammalian target of rapamycin (m TOR ) inhibitors decreases this risk. At the moment, the mechanisms behind this protective effect of m TOR inhibitors are not fully understood. We evaluated effects of the m TOR inhibitors sirolimus and everolimus on keratinocytes, c SCC cell lines and an organotypic skin model in vitro in regard to proliferation, cytokine secretion and differentiation. We show that m TOR inhibitors block keratinocyte proliferation and alter cytokine and cytokeratin production: in particular, m TOR inhibition leads to upregulation of interleukin‐6 and downregulation of cytokeratin 10. Therefore, m TOR inhibitors have effects on keratinocytes, which could play a role in the pathogenesis of c SCC .