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-α 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-α in primary DCs and found that IL-4 inhibited the initial phosphorylation of STAT1 and STAT2 (the transducers of signaling downstream of IFN-α 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.

Counter‐regulation mechanism of IL‐4 and IFN‐α signal transduction through cytosolic retention of the pY‐STAT6:pY‐STAT2:p48 complex

“…As much as the resulting retention of pY-STAT6 by pY-STAT2:p48 in the cytoplasm may lead to the suppression of IL-4 signaling into the nucleus, the retention of pY-STAT2:p48 by pY-STAT6 would have a similar role in the inhibition of nuclear localization of ISGF3 induced by IFN-a. In fact, IL-4 is shown to exert an antagonistic action on IFN-a signaling in certain cell systems [17]. As an IFN-a target gene counter-regulated by IL-4 in B lymphoma cells, IRF7 was examined.…”

“…As an IFN-a target gene counter-regulated by IL-4 in B lymphoma cells, IRF7 was examined. As a member of IRFs involved in IFN-a response, IRF7 has been reported to be induced via IFN-a-activated ISGF3 in lymphomas and DC, and to play a role in the induction of EBV-transformed lymphoma and the activation of type I IFN genes [17,36,37]. The quantitative RT-PCR analysis of IRF7 mRNA in Ramos B cells has revealed that IFN-a treatment induced IRF7 at a significant level by 4 to 8 h, and IL-4 reduced IFN-a-induced IRF7 mRNA levels in a timedependent manner (Fig.…”

“…It plays important roles in type I IFN responses such as antiviral effects and Th1 immune functions [25,26]. It was previously reported that IL-4 reduced the increment of IFN-a-induced IRF7 and IFNARs through the inhibition of the initial phosphorylation of STAT1 and STAT2, which suppressed antiviral effects by IFN-a in myeloid DC [17]. IRF7 was first identified within the biological context of EBV latency and was found to be expressed at high levels by latent membrane protein-1 to increase virally induced IFN production in EBV-transformed B cells [27,28].…”

“…IFNs and IL-4 exhibit antagonistic actions against each other in the differentiation of Th1 versus Th2 cells, IgE production, and the expression of class II MHC, IL-1R, Fc epsilon receptor II/CD23, and IFN regulatory factors (IRFs) [12][13][14][15][16][17]. Among these, the counterregulation of CD23 by IFNs and IL-4 has been widely reported.…”

“…While IFN-g induces STAT1 activation, leading to the formation of STAT1 homodimer, IFN-a induces the formation of IFN-stimulated gene factor 3 (ISGF3; STAT1:STAT2:p48) as well [9,10]. It has been recently shown that STAT4 or STAT6 can also be activated by IFN-a in certain cell types, such as lymphoid and endothelial cells [11,12].IFNs and IL-4 exhibit antagonistic actions against each other in the differentiation of Th1 versus Th2 cells, IgE production, and the expression of class II MHC, IL-1R, Fc epsilon receptor II/CD23, and IFN regulatory factors (IRFs) [12][13][14][15][16][17]. Among these, the counterregulation of CD23 by IFNs and IL-4 has been widely reported.…”