Interleukin-18 induces interferon-gamma production through NF-kappaB and NFAT activation in murine T helper type 1 cells

Cell Immunol. 1999 Aug 25;196(1):41-50. doi: 10.1006/cimm.1999.1542.


Interleukin-18 (IL-18) combined with anti-CD3 monoclonal antibody (mAb) induced interferon-gamma (IFN-gamma) production by T helper type 1 (Th1) cells. Neither IL-18 nor anti-CD3 mAb alone induced production of IFN-gamma. Although treatment with IL-18 alone induced full activation of NF-kappaB in Th1 cells, it was not sufficient for the production of IFN-gamma. To examine the importance of NF-kappaB activation in IFN-gamma production, we established Th1 cells which expressed a transdominant IkappaBalpha mutant. In these cells, activation of NF-kappaB and production of IFN-gamma by IL-18 were suppressed. On the other hand, we examined the T cell receptor (TCR)/CD3-mediated signaling pathway. FK506, an inhibitor of NFAT activation, inhibited IFN-gamma production by IL-18 without any effect on the NF-kappaB activation. We conclude that dual signaling consisting of IL-18-induced NF-kappaB activation and TCR/CD3-mediated NFAT activation is crucial for IFN-gamma production by IL-18 in murine Th1 cells.

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • CD3 Complex / immunology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • I-kappa B Proteins*
  • Interferon-gamma / biosynthesis*
  • Interleukin-18 / physiology*
  • Isoenzymes / metabolism
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Phospholipase C gamma
  • Phosphorylation
  • Signal Transduction
  • Tacrolimus / metabolism
  • Tacrolimus / pharmacology
  • Th1 Cells / drug effects
  • Th1 Cells / metabolism*
  • Transcription Factors / metabolism*
  • Transformation, Genetic
  • Type C Phospholipases / metabolism


  • Antibodies, Monoclonal
  • CD3 Complex
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Interleukin-18
  • Isoenzymes
  • NF-kappa B
  • NFATC Transcription Factors
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • NF-KappaB Inhibitor alpha
  • Interferon-gamma
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Type C Phospholipases
  • Phospholipase C gamma
  • Tacrolimus