Cyclosporin A inhibits keratinocyte cytokine gene expression

Summary The immunosuppressive peptide cyclosporin A (CyA) is an extremely effective therapy for severe recalcitrant psoriasis, although its mechanism of action is unknown. In this study, we examined the effect of CyA on keratinocyte growth and cytokine expression, and showed that CyA inhibits the growth of murine and human keratinocytes (KC) and KC cell lines. In addition, CyA inhibits the expression of cytokine genes in a dose‐dependent fashion. After 2 days' incubation with 20 μM CyA, interleukin‐lα (IL‐ α), interleukin‐1β (IL‐l β), and interleukin 8 (IL‐8) mRNA were decreased by 4‐fold, 3·3‐fold and 3·3‐fold, respectively, in COLO‐16, a keratinocyte cell line. IL‐1 biological activity recovered from COLO‐16 culture supernatants decreased to one‐fifth of that of controls. In the murine KC cell line PAM 212, 10 μ CyA treatment for 2 days downregulated IL‐1α, tumour necrosis factor‐α (TNF‐α) and IL‐1 receptor by 60%, but had no effect on the message for interleukin 3 (IL‐3), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), ornithine decarboxylase and β‐actin. Cells cultured for 5 days in the presence of CyA required much lower concentrations (2 μM) to achieve the same degree of inhibition of IL‐1α. Similar tissue concentrations of CyA have been reported in psoriatics undergoing CyA therapy. The inhibition of KC growth caused by CyA treatment could be partially overcome by the addition of 0·l–1·0 ng/ml of recombinant IL‐1α simultaneously with CyA, suggesting that the growth inhibitory effect of CyA on KC cultures is due in part to loss of autocrine cytokine stimulation. Collectively, these data suggest that CyA may exert some of its therapeutic effects in psoriasis by inhibiting the release of KC cytokines, so terminating epidermal hyperproliferation. As some of these cytokines (IL‐1, IL‐8 and TNF‐α) are chemotactic for leucocytes, or induce endothelial adhesion molecules, infiltration and inflammation may also be reduced by their inhibition.