CYCLOSPORINE-A INHIBITS KERATINOCYTE CYTOKINE GENE-EXPRESSION

The immunosuppressive peptide cyclosporin A (CyA) is an extremely effe ctive therapy for severe recalcitrant psoriasis, although its mechanis m of action is unknown. In this study, we examined the effect of CyA o n keratinocyte growth and cytokine expression, and showed that CyA inh ibits the growth of murine and human keratinocytes (KC) and KC cell li nes. In addition, CyA inhibits the expression of cytokine genes in a d ose-dependent fashion. After 2 days' incubation with 20 mu M CyA, inte rleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), and inte rleukin 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 a ctivity recovered from COLO-16 culture supernatants decreased to one-f ifth of that of controls. In the murine KC cell line PAM 212, 10 mu M CyA treatment for 2 days downregulated IL-1 alpha, tumour necrosis fac tor-alpha (TNF-alpha) and IL-1 receptor by 60%, but had no effect on t he message for interleukin 3 (IL-3), granulocyte-macrophage colony-sti mulating factor (GM-CSF), ornithine decarboxylase and beta-actin. Cell s cultured for 5 days in the presence of CyA required much lower conce ntrations (2 mu M) to achieve the same degree of inhibition of IL-1 al pha. Similar tissue concentrations of CyA have been reported in psoria tics undergoing CyA therapy. The inhibition of KC growth caused by CyA treatment could be partially overcome by the addition of 0.1-1.0 ng/m l of recombinant IL-1 alpha simultaneously with CyA, suggesting that t he growth inhibitory effect of CyA on KC cultures is due in part to lo ss of autocrine cytokine stimulation. Collectively, these data suggest that CyA, may exert some of its therapeutic effects in psoriasis by i nhibiting the release of KC cytokines, so terminating epidermal hyperp roliferation. As some of these cytokines (IL-1, IL-8 and TNF-alpha) ar e chemotactic for leucocytes, or induce endothelial adhesion molecules , infiltration and inflammation may also be reduced by their inhibitio n.