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 interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, 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 tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific 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 genes. 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 both of these stimuli requires tyrosine kinase and protein kinase activity.
Megyeri
K
K
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Au
W C
WC
Rosztoczy
I
I
Raj
N B
NB
Miller
R L
RL
Tomai
M A
MA
Pitha
P M
PM
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology*; D007372:Interferons / Q000096:biosynthesis / Q000145:classification / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000145:classification / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010222:Parainfluenza Virus 1, Human / Q000502:physiology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000634:Aminoquinolines; D016207:Cytokines; D007369:Interferon Inducers; D007378:Interleukins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons; D000077271:Imiquimod