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

Eur J Immunol. 1999 Feb;29(2):548-55. doi: 10.1002/(SICI)1521-4141(199902)29:02<548::AID-IMMU548>3.0.CO;2-Z.


IFN-gamma produced by CD4+ T helper 1 (Th1) cells promotes protection against intracellular pathogens. Antigen activation of Th1 cells is an important mode of IFN-gamma induction, but here we analyze a second, antigen-nonspecific pathway capable of inducing full IFN-gamma transcription. IL-12 or IL-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 fully induce IFN-gamma transcription independently of TCR-activated signals, by a mechanism that does not simply involve Stat4 and NF-kappaB activation, but requires additional protein synthesis. Cyclosporin A inhibits TCR-induced IFN-gamma production, but not IL-12/IL-18-induced IFN-gamma production, biochemically discriminating between these pathways. These results suggest that the two pathways induce IFN-gamma production through functionally segregated but spatially overlapping cis-acting elements, similar to other genes under the control of two or more promoters.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD4 Antigens / immunology
  • Drug Synergism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics*
  • Interferon-gamma / immunology
  • Interleukin-12 / pharmacology*
  • Interleukin-18 / pharmacology*
  • Mice
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / analysis
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Th1 Cells / immunology*


  • CD4 Antigens
  • Interleukin-18
  • RNA, Messenger
  • Interleukin-12
  • Interferon-gamma