REGULATORY EFFECTS OF ANTIPSORIATIC AGENTS ON INTERLEUKIN-1-ALPHA PRODUCTION BY HUMAN KERATINOCYTES STIMULATED WITH GAMMA-INTERFERON IN-VITRO

It is known that keratinocytes produce and secrete interleukin-1 (IL-1 ) de novo and that this process can be enhanced by various stimulators . IL-1 has been shown to be a potent proinflammatory cytokine which me diates inflammation in various cutaneous disorders. It has also been d emonstrated that gamma-interferon (IFN-gamma) which is released from i nfiltrated T cells can be detected in inflamed lesional sites. In orde r to understand the effects of IFN-gamma on IL-1 production by keratin ocytes in such inflammatory lesions, normal human keratinocytes (NHKs) and human squamous cell carcinoma cell line (HSC-1) cells were cultiv ated with recombinant human IFN-gamma (rIFN-gamma) and IL-1 levels wer e measured by ELISA. The effects of antipsoriatic agents such as hydro cortisone (HC), cyclosporin A (CsA), 1,25-dihydroxyvitamin D-3 [1,25(O H)(2)D-3] and its analogue MC903 on IL-1 production by keratinocytes w ere also investigated. IL-1 release by both NHK and HSC-1 cells was ac celerated by stimulation with rIFN-gamma dose-dependently, although IL lcr was released only transiently by rIFN-gamma-stimulated NHKs in se rum-free keratinocyte growth medium containing HC. Antihuman IFN-gamma antibody inhibited IL-1 alpha release by HSC-1 cells stimulated with rIFN-gamma, suggesting that IL-1 alpha release from keratinocytes is u pregulated by IFN-gamma. HC (5 mu g/ml), 1,25(OH)(2)D-3 (10(-6) M) and MC903 (10(-6) M), but not CsA (5 mu g/ml), inhibited IL-1 alpha produ ction by HSC-1 cells stimulated with 100 U/ml of rIFN-gamma. Since IL- 1 plays an important role in the initiation of cutaneous inflammation, its downregulation may prevent inflammation and thereby at least part ly account for the clinical effectiveness of these agents agents in th e treatment of psoriasis.