Induction of interferon-gamma production in Th1 CD4(+) T cells: evidence for two distinct pathways for promoter activation

IFN-gamma produced by CD4(+) T helper 1 (Th1) cells promotes protection aga inst intracellular pathogens. Antigen activation of Th1 cells is an importa nt mode of IFN-gamma induction, but here we analyze a second, antigen-nonsp ecific pathway capable of inducing full IFN-gamma transcription. IL-12 or I L-18 alone do not induce IFN-gamma mRNA, and only modestly augment antigen- induced IFN-gamma mRNA from Th1 cells. However, IL-12 and IL-18 together fu lly induce IFN-gamma transcription independently of TCR-activated signals, by a mechanism that does not simply involve Stat4 and NF-kappa B activation , but requires additional protein synthesis. Cyclosporin A inhibits TCR-ind uced IFN-gamma production, but not IL-12/IL-18-induced IFN-gamma production , biochemically discriminating between these pathways. These results sugges t that the two pathways induce IFN-gamma production through functionally se gregated but spatially overlapping cis-acting elements, similar to other ge nes under the control of two or more promoters.