IL-4 suppresses dendritic cell response to type I interferons

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.
The Journal of Immunology (Impact Factor: 5.36). 12/2007; 179(10):6446-55. DOI: 10.4049/jimmunol.179.10.6446
Source: PubMed

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.

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Available from: Chhanda Biswas, Aug 29, 2015
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    • "In both humans and mice, stimulation of TLR7 and TLR9 results in vigorous production of multiple pro-inflammatory cytokines such as IL-6, IL-12 and TNFα [45]. We have shown in a previous report that IL-6 is highly induced by Type I IFN stimulation, particularly by IFNβ and that IL-4 inhibits IL-6 production [29]. We analyzed the gene expression of IL-6, the two subunits of IL-12, IL-12p35 and IL-12p40, as well as TNFα in cDCs that were treated or not with IL-4 for 24 hours and then stimulated with CpG or R848 for 6 hours. "
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    • "Additionally, treatment with IFN-α or a TLR agonist was shown to differentially modulate DC maturation and immune function. In comparison to LPS stimulation, IFN-α was proposed to only partially affect DC maturation [61,62] while also inhibiting the production of IL-12 and thus potentially skewing the T helper response [63,64]. However, IFN-α is considered as a major regulator of the antiviral response and has been shown to be a potent inducer of CD8+T cell cross-priming and therefore critically required to induce DC full maturation upon engagement of a TLR [65-67]. "
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