Sriram Uma, Biswas Chhanda, Behrens Edward M, Dinnall Joudy-Ann, Shivers Debra K, Monestier Marc, Argon Yair, Gallucci Stefania
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.
J Immunol. 2007 Nov 15;179(10):6446-55. doi: 10.4049/jimmunol.179.10.6446.
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.
细胞因子在调节树突状细胞（DCs）的发育和功能中发挥着重要作用。I型干扰素激活DCs并驱动抗病毒反应，而IL-4是Th2细胞因子的原型。有证据表明，I型干扰素和IL-4相互影响以调节DC功能。我们发现，两种I型干扰素，IFN-α和IFN-β，在髓样静息DCs中刺激了相似的共刺激谱。IL-4在体外和体内通过损害MHC和共刺激分子的上调以及细胞因子（如IL-6和IL-15）和抗病毒基因（如Mx-1）在I型干扰素刺激下的产生，抑制了髓样DCs对两种I型干扰素的反应。在剖析这种抑制的潜在机制时，我们对原代DCs中由IFN-α触发的正反馈回路进行了表征，发现IL-4抑制了STAT1和STAT2（IFN-α和-β受体（IFNARs）下游的信号转导分子）的初始磷酸化，并在体外和体内降低了参与IFN反应放大的基因（如IRF-7、STAT1、STAT2、IFN-β和IFNARs）的上调。因此，IL-4使髓样DCs对旁分泌I型干扰素的反应性降低，并且在维持通常放大I型干扰素作用的自分泌正反馈回路方面效力降低。这种抑制可以解释在诱导Th2的寄生虫感染期间观察到的对病毒感染易感性增加的现象。
