Effect of a Novel Topical Immunomodulator, S-28463, on Keratinocyte Cytokine Gene Expression and Production

Abstract

A new immunomodulating agent, imiquimod, has been reported to have antiviral and antitumor activities in animal models. S-28463 (4-amino-2-ethoxymethyl-α, α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol), an analog of imiquimod, has more potent antiviral activity in animals than imiquimod. It has also been shown to be more potent at inducing cytokines in human blood in vitro. However, its precise role as an immunomodulator in the skin has not been determined. We investigated the effect of S-28463 on human keratinocyte (KC) production of interferon-α (IFN-α) and other proinflammatory cytokines, including interleukin (IL)-1α, IL-8, and tumor necrosis factor-α (TNF-α). Human KC were incubated with S-28463 at two concentrations (1 μg/ml and 10 μg/ml) for 6 h. Cytokine gene expression was analyzed by reverse-transcriptase PCR. In human KC, S-28463 stimulated significant increases in IFN-α mRNA at both concentrations. IL-1α mRNA increased 1.4-fold at 10 μg/ml. IL-8 mRNA was upregulated 2.5-fold at 10 μg/ml. Twenty-four hours after treatment, IL-1α, IL-8, and TNF-α protein were increased, but IFN-α was below the level of detection. These results suggest that in the skin, S-28463-induced-IL-1α, IL-8, and TNF-α production may be involved in the immunomodulating action of S-28463.