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IL-4 Suppresses Dendritic Cell Response to Type I Interferons¹

Uma Sriram^*, Chhanda Biswas, Edward M. Behrens^*, Joudy-Ann Dinnall^*, Debra K. Shivers^*, Marc Monestier, Yair Argon and Stefania Gallucci^2,*

^* Laboratory of Dendritic Cell Biology, Joseph Stokes Jr. Research Institute, Division of Rheumatology, Department of Pediatrics, Division of Cell Pathology, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, and Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140

Cytokines play an important role in modulating the development and function of dendritic cells (DCs). Type I IFNs activate DCs and drive anti-viral responses, whereas IL-4 is the prototype of a Th2 cytokine. Evidence suggests that type I IFNs and IL-4 influence each other to modulate DC functions. We found that two type I IFNs, IFN- and IFN-β, stimulated a similar costimulatory profile in myeloid resting DCs. IL-4 suppressed the response of myeloid DCs to both type I IFNs in vitro and in vivo by impairing the up-regulation of MHC and costimulatory molecules and the production of cytokines, such as IL-6 and IL-15, and anti-viral genes, such as Mx-1, upon type I IFN stimulation. In dissecting the mechanism underlying this inhibition, we characterized the positive feedback loop that is triggered by IFN- in primary DCs and found that IL-4 inhibited the initial phosphorylation of STAT1 and STAT2 (the transducers of signaling downstream of IFN- and -β receptors (IFNARs)) and reduced the up-regulation of genes involved in the amplification of the IFN response such as IRF-7, STAT1, STAT2, IFN-β, and the IFNARs in vitro and in vivo. Therefore, IL-4 renders myeloid DCs less responsive to paracrine type I IFNs and less potent in sustaining the autocrine positive loop that normally amplifies the effects of type I IFNs. This inhibition could explain the increased susceptibility to viral infections observed during Th2-inducing parasitoses.

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.

¹ This work was supported by National Institutes of Health National Institute of Allergy and Infectious Diseases Grant AI049892 (to S.G.), the Lupus Foundation Southeastern Pennsylvania Chapter, the Arthritis Foundation (Innovative Grant to S.G.), and by a grant from the Pennsylvania Department of Health. U.S. was supported by a postdoctoral fellowship from the Arthritis Foundation. E.M.B. was supported by National Institute of Health Grant T32-HD0043021. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.

² Address correspondence and reprint requests to Dr. Stefania Gallucci, 1107C Abramson Research Center, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: gallucci{at}email.chop.edu

³ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; Ct, threshold cycle; IFNAR, IFN- and -β receptor; IRF, IFN regulatory factor; KO, knockout; MdFI, median fluorescence intensity; Mx, myxovirus resistance.