Sustained IL-12 Signaling Is Required for Th1 Development (2004)

Author(s): Athie-Morales V, Smits HH, Cantrell DA, Hilkens CM

  • : Sustained IL-12 signaling is required for Th1 development

Abstract: STAT4 is an essential transcription factor for Th1 cell development. IL-12 and IFN-alpha both activate STAT4, but with different kinetics. In this study we compared their capacities to drive differentiation of human naive Th cells toward the Th1 phenotype. The Th1-polarizing activity of IFN-alpha was much weaker than that of IL-12, correlating with a marked difference in the kinetics of STAT4 activation; the response to IL-12 was sustained (>48 h), whereas the response to IFN-alpha was transient (4 h). The continuous presence of IL-12 was required for sustained STAT4 activation. Similarly, optimal Th1 polarization was only achieved upon prolonged exposure to IL-12 and could not be induced by a transient IL-12 pulse. Furthermore, the cytokine IL-2 potentiated sustained IL-12/STAT4 responses through up-regulation of IL-12R expression and synergized with IL-12 in driving Th1 cell development. Transient IFN-alpha responses, on the other hand, were not prolonged by IL-2. IFN-alpha treatment induced down-regulation of IFN-alphabeta receptor subunit 1, rendering cells refractory to IFN-alpha, but did not trans-inhibit the IL-12/STAT4 response. These data indicate that sustained IL-12 signaling is essential for optimal Th1 cell development and that transient activation of STAT4 in response to IFN-alpha may explain the poor Th1-polarizing capacity of this cytokine. Collectively these data show that the duration of cytokine signaling is important for determining the biological response.

Notes: 0022-1767 Journal Article

  • Short Title: Sustained IL-12 signaling is required for Th1 development
  • Date: 2004-01-01
  • Journal: Journal of Immunology
  • Volume: 172
  • Issue: 1
  • Pages: 61-69
  • Publisher: American Association of Immunologists
  • Publication type: Article
  • Bibliographic status: Published

Keywords: Adjuvants, Immunologic/pharmacology/physiology Biological Response Modifiers/pharmacology/physiology Cell Differentiation/*immunology Cell Division/immunology Comparative Study DNA-Binding Proteins/pharmacology Drug Synergism Flow Cytometry Human Interferon-alpha/pharmacology Interleukin-12/pharmacology/*physiology Interleukin-2/pharmacology Interphase/immunology Signal Transduction/*immunology Support, Non-U.S. Gov't T-Lymphocytes, Helper-Inducer/cytology/immunology/metabolism Th1 Cells/*cytology/*immunology/metabolism Time Factors Trans-Activators/pharmacology


Dr Catharien Hilkens
Reader in Immunotherapy