A mechanism underlying STAT4-mediated up-regulation of IFN-gamma induction inTCR-triggered T cells

Int Immunol. 2004 Feb;16(2):295-302. doi: 10.1093/intimm/dxh034.

Abstract

IL-12 promotes T(h)1 development/IFN-gamma expression by activating STAT4. However, it is still unclear how STAT4 elicits IFN-gamma promoter activation. Here, we investigated the mechanism by which IL-12-activated STAT4 functions for IFN-gamma induction in TCR-triggered T cells. TCR stimulation induced high levels of IFN-gamma production depending on co-stimulation with IL-12. IL-12 stimulation greatly enhanced the promoter-binding activity of c-Jun/AP-1, a critical transcription factor for IFN-gamma gene expression in wild-type T cells, but not in STAT4-deficient (STAT4(-/-)) T cells. Comparable amounts of c-Jun were induced by TCR stimulation in both wild-type and STAT4(-/-) T cells irrespective of IL-12 co-stimulation. However, c-Jun bound to STAT4 in IL-12-co-stimulated wild-type T cells. c-Jun forming a complex with STAT4 efficiently interacted with the AP-1-related sequence of the IFN-gamma promoter. Such an enhanced c-Jun binding did not occur in STAT4(-/-) T cells. These results show that STAT4 contributes to enhancing IFN-gamma expression by up-regulating the binding of TCR signal-induced AP-1 to the relevant promoter sequence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • CD3 Complex / immunology
  • CD3 Complex / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Genes, jun / genetics
  • Genes, jun / physiology
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Interleukin-12 / pharmacology*
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation / drug effects
  • Protein Binding / physiology
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-12
  • STAT4 Transcription Factor
  • Th1 Cells / immunology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism

Substances

  • Antibodies, Monoclonal
  • CD28 Antigens
  • CD3 Complex
  • DNA-Binding Proteins
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Trans-Activators
  • Transcription Factor AP-1
  • Interleukin-12
  • Interferon-gamma