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.

Original languageEnglish
Pages (from-to)548-555
Number of pages8
JournalEuropean Journal of Immunology
Issue number2
StatePublished - 1999


  • Cytokine
  • IFN-γ
  • IL-12
  • IL-18
  • Th1


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