IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-γ expression in murine NK cells

Jay H. Bream, Rafael E. Curiel, Cheng Rong Yu, Charles E. Egwuagu, Michael J. Grusby, Thomas M. Aune, Howard A. Young

Research output: Contribution to journalArticle

Abstract

Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)-type cytokines like interferon-γ (IFN-γ). While investigating IL-4 regulation of IFN-γ expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN-γ production and mRNA expression in spleen-derived, IL-2 - cultured NK cells, as well as negatively sorted fresh DX5+/CD3- NK cells albeit at lower levels. The positive effect of IL-4 on IL-2-induced IFN-γ production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6-/- mice. Notably, though, IL-12 plus IL-4 synergy on IFN-γ expression was intact in Stat6-/- mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN-γ promoter that may be involved, NK cells from human IFN-γ promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN-γ promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN-γ expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations.

Original languageEnglish (US)
Pages (from-to)207-214
Number of pages8
JournalBlood
Volume102
Issue number1
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Bream, J. H., Curiel, R. E., Yu, C. R., Egwuagu, C. E., Grusby, M. J., Aune, T. M., & Young, H. A. (2003). IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-γ expression in murine NK cells. Blood, 102(1), 207-214. https://doi.org/10.1182/blood-2002-08-2602