Distinct characteristics of murine STAT4 activation in response to IL-12 and IFN-alpha.
The role of type I IFN in Th1 development, STAT4 activation, and IFN-gamma production in murine T cells has remained unresolved despite extensive examination. Initial studies indicated that IFN-alpha induced Th1 development and IFN-gamma production in human, but not murine, T cells, suggesting species-specific differences in signaling. Later studies suggested that IFN-alpha also induced Th1 development in mice, similar to IL-12. More recent studies have questioned whether IFN-alpha actually induces Th1 development even in the human system. In the present study, we compared the capacity of IL-12 and IFN-alpha to induce Th1 differentiation, STAT4 phosphorylation, and IFN-gamma production in murine T cells. First, we show that IFN-alpha, in contrast to IL-12, cannot induce Th1 development. However, in differentiated Th1 cells, IFN-alpha can induce transient, but not sustained, STAT4 phosphorylation and, in synergy with IL-18, can induce transient, but not sustained, IFN-gamma production in Th1 cells, in contrast to the sustained actions of IL-12. Furthermore, loss of STAT1 increases IFN-alpha-induced STAT4 phosphorylation, but does not generate levels of STAT4 activation or IFN-gamma production achieved by IL-12 or convert transient STAT4 activation into a sustained response. Our findings agree with recent observations in human T cells that IFN-alpha-induced STAT4 activation is transient and unable to induce Th1 development, and indicate that IFN-alpha may act similarly in human and murine T cells.
Berenson
Lisa S
LS
Department of Pathology and Center for Immunology, Washington University of School of Medicine, St Louis, MO 63110, USA.
Gavrieli
Maya
M
Farrar
J David
JD
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D016898:Interferon-alpha / Q000096:biosynthesis / Q000494:pharmacology*; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D013045:Species Specificity; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects*
D016898:Interferon-alpha; D050797:STAT4 Transcription Factor; D018664:Interleukin-12