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J. Biol. Chem., Vol. 279, Issue 1, 169-176, January 2, 2004

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Bi-phasic Effect of Interferon (IFN)-

IFN- UP- AND DOWN-REGULATES INTERLEUKIN-4 SIGNALING IN HUMAN T CELLS^*

Karsten Wessel Eriksen, Viveca Horst Sommer, Anders Woetmann, Anette Bødker Rasmussen, Christine Brender, Arne Svejgaard, Søren Skov, Carsten Geisler, and Niels Ødum¶

From the Institute of Medical Microbiology and Immunology, and Institute of Molecular Biology, University of Copenhagen and the Department of Clinical Immunology, National University Hospital, DK2200 Copenhagen, Denmark

Interferon (IFN)-/ 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-/ inhibits interleukin (IL)-4 signaling in B cells and monocytes, suggesting that IFN-/ (like IFN-) is a Th1 cytokine. Here, we study cross-talk between IFN- and IL-4 in human T cells. As expected, stimulation with IFN- for 12–24 h inhibits IL-4 signaling. Surprisingly, however, IFN- has the opposite effect on IL-4 signaling at earlier time points (up to 6 h). Thus, IFN- enhances IL-4-mediated STAT6 activation in both CD4+ and CD8+ human T cells. The effect is specific because (i) another interferon, IFN-, does not enhance IL-4-mediated STAT6 activation, (ii) IFN--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- 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-4R and IL-15R). In conclusion, we provide evidence that IFN- 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- has a complex regulatory role in adaptive immunity, which is different from the "classical" Th1 profile of IFN-.

Received for publication, September 22, 2003

^* This work was supported in part by funds from the University of Copenhagen Ph.D. program (to K. W. E., A. W., and C. B.), the Danish Allergy Research Center, the Danish Research Councils, the Danish Biotechnological Center for Cellular Communication, the Danish Biotechnology Program, the Novo Nordic Foundation, Becketts Fond, the Danish Medical Associations Research Foundation, the Danish Cancer Research Foundation (Dansk Kræftsforsknings Fond), the Danish Cancer Society (Kræftens Bekæmpelse), the Alfred Benzon Foundation, the Dannins Foundation (Ingeborg og Leo Dannins Legat for Videnskabelig Forskning), Gerda and Aage Haensch's Foundation, and the Johann Weiman F. Seedorff and Wife Foundation (Købmand i Odense Johann og Hanne Weimann f. Seedorff's Legat). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Institute of Medical Microbiology and Immunology, Panum 22.5.34, University of Copenhagen, Blegdamsvej 3c, DK2200 Copenhagen, Denmark. Tel.: 45-3532-7879; Fax: 45-3532-7876; E-mail: n.odum{at}immi.ku.dk.

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