Additive and synergistic antiproliferative effects of cyclosporin A and gamma interferon on cultured human keratinocytes.

To examine whether keratinocytes (KC) may be a cellular target for the action of cyclosporin A (CsA) in psoriasis and other skin diseases, the direct antiproliferative effect of CsA was examined on rapidly proliferating KCs grown on plastic in serum-free media. CsA at concentrations of 1-10 micrograms/ml directly inhibited KC proliferation over an 8-day incubation period. CsH, an immunologically inert stereoisomer, also inhibited KC proliferation at 5-10 micrograms/ml. When CsA (1 microgram/ml) was combined with gamma-interferon (gamma-IFN; 100 units/ml), there was an additive cytostatic effect on KC proliferation. The potentiating properties of gamma-IFN (100 U/ml) were additive when combined with CsA (1 microgram/ml) and synergistic at a higher concentration of CsA (5 micrograms/ml). The cytostatic effect of CsA (5 micrograms/ml) on KC proliferation was reversible after removal of the drug. Exposure of KCs to CsA resulted in numerous lipid-laden cytoplasmic vacuoles, which began to appear after 24 hours of CsA treatment. The fact that previous reports have documented 1-3 micrograms/ml of CsA and 100 U/ml of gamma-IFN in skin lesions of psoriasis patients suggests that our in vitro results were obtained with the use of physiologically relevant concentrations of these molecules. The direct antiproliferative effects by CsA on KCs suggest that both KCs and lymphocytes may be cellular targets in vivo for the mechanism of action of CsA in psoriasis.