title: IL-4 suppresses dendritic cell response to type I interferons.
abstract: 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-alpha and IFN-beta, 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-alpha in primary DCs and found that IL-4 inhibited the initial phosphorylation of STAT1 and STAT2 (the transducers of signaling downstream of IFN-alpha and -beta receptors (IFNARs)) and reduced the up-regulation of genes involved in the amplification of the IFN response such as IRF-7, STAT1, STAT2, IFN-beta, 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.
authors.affiliation: Laboratory of Dendritic Cell Biology, Joseph Stokes Jr. Research Institute, Division of Rheumatology, Department of Pediatrics, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Sriram
authors.forename: Chhanda
authors.initials: C
authors.lastname: Biswas
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
authors.forename: Joudy-Ann
authors.initials: JA
authors.lastname: Dinnall
authors.forename: Debra K
authors.initials: DK
authors.lastname: Shivers
authors.forename: Marc
authors.initials: M
authors.lastname: Monestier
authors.forename: Yair
authors.initials: Y
authors.lastname: Argon
authors.forename: Stefania
authors.initials: S
authors.lastname: Gallucci
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D019204:GTP-Binding Proteins / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology* / Q000494:pharmacology; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology; D019409:Interleukin-15 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology* / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D064547:Myxovirus Resistance Proteins; D019899:Paracrine Communication / Q000187:drug effects / Q000276:immunology; D010273:Parasitic Diseases, Animal / Q000276:immunology; D017471:Receptors, Interferon / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology; D050795:STAT2 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology
chemical_list: D006649:Histocompatibility Antigens; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D019409:Interleukin-15; D015850:Interleukin-6; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; D015847:Interleukin-4; D016899:Interferon-beta; D019204:GTP-Binding Proteins