IFN-γ produced by CD4+ T helper 1 (Th1) cells promotes protection against intracellular pathogens. Antigen activation of Th1 cells is an important mode of IFN-γ induction, but here we analyze a second, antigen-nonspecific pathway capable of inducing full IFN-γ transcription. IL-12 or IL-18 alone do not induce IFN-γ mRNA, and only modestly augment antigen-induced IFN-γ mRNA from Th1 cells. However, IL-12 and IL-18 together fully induce IFN-γ transcription independently of TCR-activated signals, by a mechanism that does not simply involve Stat4 and NF-κB activation, but requires additional protein synthesis. Cyclosporin A inhibits TCR-induced IFN-γ production, but not IL-12/IL-18-induced IFN-γ production, biochemically discriminating between these pathways. These results suggest that the two path ways induce IFN-γ production through functionally segregated but spatially overlapping cis-acting elements, similar to other genes under the control of two or more promoters.
|Number of pages||8|
|Journal||European Journal of Immunology|
|State||Published - 1999|