STIMULATION OF INTERFERON AND CYTOKINE GENE-EXPRESSION BY IMIQUIMOD AND STIMULATION BY SENDAI VIRUS UTILIZE SIMILAR SIGNAL-TRANSDUCTION PATHWAYS

The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha in terferon (IFN-alpha) synthesis both in vivo and in peripheral blood mo nonuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFN A5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyros ine kinase and protein kinase C inhibitors. Infection with Sendai viru s led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-spec ific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes , but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA ge nes. These results indicate that imiquimod, similar to viral infection , stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by b oth of these stimuli requires tyrosine kinase and protein kinase activ ity.