Gene expression in actinic keratoses: pharmacological modulation by imiquimod

Actinic keratoses (AKs) are premalignant lesions that can progress into squamous cell carcinoma. Imiquimod, which belongs to the new class of immune-response modifiers, was recently shown to be effective in the treatment of AKs. The underlying mechanisms are not fully understood.

To study the expression of individual genes in uninvolved skin and AKs before therapy and to elucidate the way in which the expression of these genes is influenced by imiquimod therapy.

We treated 13 patients with AK with imiquimod and compared gene expression before, during (five patients) and after (eight patients) therapy with that in uninvolved skin. We analysed genes coding for inflammatory cytokines or their receptors, adhesion molecules, anti-apoptotic proteins, p53 and toll-like receptors (TLRs) by reverse-transcriptase polymerase chain reaction.

Comparing uninvolved skin and untreated AK, we found significant differences in the expression of interleukin (IL)-6, hurpin, TLR7 and TLR8. During imiquimod therapy, we detected a further upregulation of interferon-alpha, IL-6, IL-10 receptor 1 and TLR7. In contrast, two anti-apoptotic genes, hurpin and HAX-1, were downregulated. We did not detect significant differences in gene expression for p53, tumour necrosis factor-alpha and alpha- and beta-catenins. Clinically, the upregulated expression of the proinflammatory cytokines correlated with the local inflammation induced by imiquimod.

Our results indicate that specific differences in gene expression are detectable between AK and uninvolved skin. Imiquimod influenced the expression of most genes analysed in this study. This work extends previous findings on the effects of imiquimod on gene regulation in AKs.