Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor-dependent innate antiviral immune responses
Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor-dependent innate antiviral immune responses
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DOI：
10.1016/j.jaci.2006.08.006
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发表时间：
2006-12-01
影响因子：
14.2
通讯作者：
Geha, Raif S.
中科院分区：
文献类型：
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作者：
McDonald, Douglas R.;Brown, Daniel;Geha, Raif S.
背景：所有已知的Toll样受体(TLRs)的结合都会导致炎性细胞因子的产生，包括肿瘤坏死因子-α，而在人类中，TLRs 3、7、8和9的结合也会诱导I型IFN。IRAK-4是TLRs和IL-1受体信号通路中的关键效应者，两者在细胞内结构域具有同源性，并通过接头髓系分化因子88(MyD88)招募IRAK-4。IRAK-4缺乏的患者容易受到侵袭性细菌感染，但到目前为止还没有报告说对病毒感染敏感。这些患者的血细胞产生肿瘤坏死因子-α的能力受到损害，以应对TLRs的激活。最近的一份报告描述了TLR7、8和9激活后伴随的I型干扰素产生的损害，但TLR3没有。目的：我们试图评估IRAK-4在TLR诱导的人类I型干扰素-α产生中的作用。方法：我们检测了一名IRAK-4缺陷患者、其杂合携带者父母和正常对照组PBMC中TLR诱导的肿瘤坏死因子-α和干扰素-α的产生。TLR7、TLR8和TLR9以及TLR3激动剂诱导的干扰素-α产生很少或不产生。结论：IRAK-4在包括TLR3在内的所有TLRs诱导的I型干扰素和肿瘤坏死因子-α的产生中起重要作用。
Background: Engagement of all known Toll-like receptors (TLRs) causes the production of inflammatory cytokines, including TNF-alpha, whereas in humans, engagement of TLRs 3, 7, 8, and 9 also induces type I IFNs. IRAK-4 is a critical effector in signaling by TLRs and the IL-1 receptor, which share homology in their intracellular domain and recruit IRAK-4 via the adaptor myeloid differentiation factor 88 (MyD88). Patients with IRAK-4 deficiency are susceptible to invasive bacterial infections but have so far not been reported to be susceptible to viral infection. Blood cells from these patients are impaired in their ability to make TNF-alpha in response to activation by TLRs. A recent report has described concomitant impairment of type I IFN production after activation of TLRs 7, 8, and 9, but not TLR3.Objectives: We sought to evaluate the role of IRAK-4 in TLR-induced production of the type I IFN, IFN-alpha, in humans.Methods: We examined TLR-induced production of TNF-a and IFN-alpha in PBMCs from an IRAK-4-deficient patient, his heterozygous carrier parents, and normal controls.Results: TNF-alpha production in response to TLR agonists was severely impaired in the patient. IFN-alpha production induced by TLR7, TLR8, and TLR9, as well as TLR3 agonists, was low or absent. Conclusions: IRAK-4 plays an important role in the production of type I IFN, as well as TNF-a, induced by all TLRs, including TLR3.Clinical implications: IRAK-4 may play a broader role in human innate antiviral immunity than previously appreciated.