Bi-phasic effect of interferon (IFN)-alpha: IFN-alpha up- and down-regulates interleukin-4 signaling in human T cells.
Interferon (IFN)-alpha/beta is produced by virally infected cells and is believed to play an important role in early phases of the innate immune response. In addition, IFN-alpha/beta inhibits interleukin (IL)-4 signaling in B cells and monocytes, suggesting that IFN-alpha/beta (like IFN-gamma) is a Th1 cytokine. Here, we study cross-talk between IFN-alpha and IL-4 in human T cells. As expected, stimulation with IFN-alpha for 12-24 h inhibits IL-4 signaling. Surprisingly, however, IFN-alpha has the opposite effect on IL-4 signaling at earlier time points (up to 6 h). Thus, IFN-alpha enhances IL-4-mediated STAT6 activation in both CD4+ and CD8+ human T cells. The effect is specific because (i) another interferon, IFN-gamma, does not enhance IL-4-mediated STAT6 activation, (ii) IFN-alpha-mediated STAT1 and STAT2 activation is not modulated by IL-4, and (iii) activation of Janus kinases is not enhanced or prolonged by simultaneous stimulation with IFN-alpha and IL-4. Moreover, co-stimulation results in a selective increased STAT6/STAT2 association and an association between IFNAR/IL-4R components, suggesting that the IFNAR provides an additional STAT6 docking site via STAT2, leading to a more efficient dimerization/activation of STAT6 only. The co-stimulatory effect on STAT6 activation correlates with a cooperative increase in nuclear translocation, DNA binding, transcriptional activity, and mRNA expression of STAT6 target genes (IL-4Ralpha and IL-15Ralpha). In conclusion, we provide evidence that IFN-alpha both up- and down-regulates IL-4-mediated STAT6 signaling and thereby regulates the sensitivity to IL-4 in human T lymphocytes. Thus, our findings suggest that IFN-alpha has a complex regulatory role in adaptive immunity, which is different from the "classical" Th1 profile of IFN-gamma.
Eriksen
Karsten Wessel
KW
Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
Sommer
Viveca Horst
VH
Woetmann
Anders
A
Rasmussen
Anette Bødker
AB
Brender
Christine
C
Svejgaard
Arne
A
Skov
Søren
S
Geisler
Carsten
C
Ødum
Niels
N
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D015847:Interleukin-4 / Q000276:immunology* / Q000494:pharmacology; D018448:Models, Immunological; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism
D004268:DNA-Binding Proteins; D007370:Interferon Type I; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4