CYTOKINE INDUCTION IN HAIRLESS MOUSE AND RAT SKIN AFTER TOPICAL APPLICATION OF THE IMMUNE-RESPONSE MODIFIERS IMIQUIMOD AND S-28463

ALDARA (imiquimod cream 5%) recently became available for the treatmen t of genital and perianal warts; however, the topical mechanism of act ion of imiquimod is not fully understood. Imiquimod, and its analogs R -842, S-27609, and S-28463, are potent anti-viral and anti-tumor agent s in animal models. Much of the biologic activity of these compounds c an be attributed to the induction of cytokines, including interferon-a lpha, tumor necrosis factor-alpha, interleukins-1, -6, -8, and others. This study was performed to characterize the response of mice and rat s to topical application of imiquimod and S-28463 and also to evaluate these agents in cultures of murine and human skin cells. Topical admi nistration of imiquimod or S-28463 to the flanks of hairless mice and rats leads to increases in local concentrations of interferon and tumo r necrosis factor in the skin. The concentrations of interferon and tu mor necrosis factor were higher at the site of drug application than i n skin from the contralateral flank or skin from untreated animals. In terferon-alpha mRNA levels were also elevated in the skin of mice afte r topical application of either imiquimod or S-28463. In vitro, both i miquimod and S-28463 induced increases in interferon and tumor necrosi s factor in cultures of cells isolated from hairless mouse skin. Imiqu imod also increased interleukin-8 concentrations in human keratinocyte and fibroblast cultures, whereas S-28463 induced increases in tumor n ecrosis factor in fibroblast cultures. These results demonstrate that imiquimod and S-28463 stimulate production of cytokines in the skin af ter topical application, which may play a major role in its activity i n genital wart patients.