Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation
Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation
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DOI：
10.1074/jbc.m407640200
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发表时间：
2004-10-15
影响因子：
4.8
通讯作者：
Hahn, YS
中科院分区：
文献类型：
--
作者：
Eisen-Vandervelde, AL;Waggoner, SN;Hahn, YS
丙型肝炎病毒（HCV）在建立持续感染方面非常有效，这表明它已经进化出一种或多种旨在逃避宿主免疫反应的策略。T细胞反应，包括干扰素γ的产生，在慢性HCV患者中受到严重抑制。HCV核心蛋白先前已被证明在HCV感染患者的血液中循环，并通过与gC1qR的相互作用抑制宿主免疫。为了确定HCV核心- gc1qr相互作用在炎症细胞因子产生调节中的作用，我们在脂多糖刺激的人类单核细胞/巨噬细胞中检测了白细胞介素(IL)-12的产生，IL -12对于诱导干扰素γ合成至关重要。我们发现核心蛋白与单核/巨噬细胞表面显示的gC1qR结合，并在脂多糖刺激下抑制IL-12p70的产生。这种抑制被发现是选择性的，因为HCV核心不能影响IL-6、IL-8、il -1 β和肿瘤坏死因子α的产生。此外，通过抑制il - 12p40mrna的合成，核心蛋白在转录水平上抑制IL-12的产生。重要的是，核心诱导的IL-12p40 mRNA合成抑制是由于AP-1激活受损，而不是IL-10生成增强。这些结果表明，HCV核心- gc1qr相互作用可能通过抑制TH1反应在建立持续感染中发挥关键作用。
Hepatitis C virus (HCV) is remarkably efficient at establishing persistent infection, suggesting that it has evolved one or more strategies aimed at evading the host immune response. T cell responses, including interferon-gamma production, are severely suppressed in chronic HCV patients. The HCV core protein has been previously shown to circulate in the bloodstream of HCV-infected patients and inhibit host immunity through an interaction with gC1qR. To determine the role of the HCV core-gC1qR interaction in modulation of inflammatory cytokine production, we examined interleukin (IL)-12 production, which is critical for the induction of interferon-gamma synthesis, in lipopolysaccharide-stimulated human monocyte/macrophages. We found that core protein binds the gC1qR displayed on the cell surface of monocyte/macrophages and inhibits the production of IL-12p70 upon lipopolysaccharide stimulation. This inhibition was found to be selective in that HCV core failed to affect the production of IL-6, IL-8, IL-1beta, and tumor necrosis factor alpha. In addition, suppression of IL-12 production by core protein occurred at the transcriptional level by inhibition of IL-12p40 mRNA synthesis. Importantly, core-induced inhibition of IL-12p40 mRNA synthesis resulted from impaired activation of AP-1 rather than enhanced IL-10 production. These results suggest that the HCV core-gC1qR interaction may play a pivotal role in establishing persistent infection by dampening TH1 responses.