CD46-utilizing adenoviruses inhibit C/EBPβ-dependent expression of proinflammatory cytokines
CD46-utilizing adenoviruses inhibit C/EBPβ-dependent expression of proinflammatory cytokines
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DOI：
10.1128/jvi.79.17.11259-11268.2005
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发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
Nemerow, GR
中科院分区：
文献类型：
--
作者：
Iacobelli-Martinez, M;Nepomuceno, RR;Nemerow, GR
大多数腺病毒血清型利用柯萨奇病毒-腺病毒受体(CAR)来连接病毒-宿主细胞，但B亚组和D亚组(腺病毒37[AD37])病毒识别CD46。CD46是一种普遍表达的受体，是补体成分Cab和Cob失活的辅助因子，也是多种微生物病原体的受体。据报道，CD46参与的一个后果是人类免疫细胞表达白介素12(IL-12)的能力降低，白介素12是一种参与先天性和获得性免疫反应的细胞因子。因此，进行了研究以确定利用CD46的ADS是否改变了促炎细胞因子的表达。B亚群(Ad16和-35)和AD37，而不是AD2或-5，显著减少了人外周血单个核细胞在干扰素和脂多糖刺激下产生的IL-12。IL-12mRNA(p35和p40亚单位)水平以及其他细胞因子mRNA水平(IL-1α和-β、IL-1ra和IL-6)在与利用CD46的Ads相互作用后降低。对细胞因子表达所需转录因子活性的分析表明，利用CD46的ADS优先抑制干扰素-γ诱导的C/EBPβ蛋白的表达，从而降低其形成DNA复合体的能力。利用CD46的Ads对干扰素-γ信号事件的干扰，而不是利用汽车的Ads，揭示了宿主对不同Ad载体的免疫反应的潜在关键差异，这种情况对基因传递和疫苗开发具有意义。
The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus receptor (CAR) for virus-host cell attachment, but subgroup B and subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46 is a ubiquitously expressed receptor that serves as a cofactor for the inactivation of the complement components Cab and Cob, and it also serves as a receptor for diverse microbial pathogens. A reported consequence of CD46 engagement is a reduced capability of human immune cells to express interleukin-12 (IL-12), a cytokine involved in both the innate and adaptive immune responses. Studies were thus undertaken to determine whether CD46-utilizing Ads alter the expression of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37, but not Ad2 or -5, significantly reduced IL-12 production by human peripheral blood mononuclear cells stimulated with gamma interferon (IFN-gamma) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits) levels as well as other cytokine mRNA levels (IL-1 alpha) and -beta, IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing Ads. Analysis of transcription factor activity required for cytokine expression indicated that CD46-utilizing Ads preferentially inhibited IFN-gamma-induced C/EBP beta protein expression, consequently reducing its ability to form DNA complexes. Interference with IFN-gamma signaling events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals a potentially critical difference in the host immune response against distinct Ad vectors, a situation that has implications for gene delivery and vaccine development.