CYTOKINE INDUCTION BY THE IMMUNOMODULATORS IMIQUIMOD AND S-27609

Imiquimod (R-837, S-26308) and the analogue S-27609 were evaluated for cytokine induction in human blood cells, Both compounds induced inter feron-alpha (IFN), tumor necrosis factor-alpha (TNF), interleukin (IL) -1 beta, and IL-6 with S-27609 being 5 to 10 times more potent, Imiqui mod and S-27609 also induced IL-1 alpha, IL-1 receptor antagonist, IL- 10, granulocyte-macrophage colony-stimulating factor (GM-CSF), ganuloc yte CSF (G-CSF), and macrophage inflammatory protein-1 alpha. The prof ile of cytokines induced by imiquimod and S-27609 was different from t hose seen with lipopolysaccharide and polyinosinic-polycytidylic acid, Kinetic studies with both imiquimod mod and S-27609 revealed inductio n of cytokines as early as 1-4 h after stimulation, Although most of t he cytokines produced by S-27609 were secreted, significant concentrat ions of IL-1 alpha and IL-1 beta remained intracellular. Monocytes wer e largely responsible for the cytokines produced. Finally, S-27609-ind uced mRNA expression for TNF, IFN, and IL-8, and this induction did no t require protein synthesis. Taken together, these studies extend prev ious findings by showing induction of additional cytokines and providi ng insight into the mechanism of cytokine induction by these molecules .