Interferon-Gamma Enhances TLR3 Expression and Anti-Viral Activity in Keratinocytes
Interferon-Gamma Enhances TLR3 Expression and Anti-Viral Activity in Keratinocytes
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DOI：
10.1038/jid.2015.125
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发表时间：
2015-08-01
影响因子：
6.5
通讯作者：
Iwatsuki, Keiji
中科院分区：
文献类型：
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作者：
Kajita, Ai;Morizane, Shin;Iwatsuki, Keiji
Toll样受体（TLR）识别先天免疫应答中的特定微生物产物。TLR 3是一种双链RNA传感器，被认为在病毒感染中具有重要作用，但TLR 3在角质形成细胞中的表达调控及其功能尚未完全了解。在这里，我们表明，在培养的正常人表皮角质形成细胞（NHEK）中，Th 1细胞因子IFN-γ通过STAT 1增加TLR 3的表达。与单独的poly（I：C）或IFN-γ相比，IFN-γ和TLR 3配体poly（I：C）的共刺激协同增加了NHEK中IFN-β、IL-6、IL-8和人β-防御素-2的表达。这些协同诱导被内体酸化抑制剂氯喹和TLR 3 siRNA显著抑制。与单独的poly（I：C）或IFN-γ相比，IFN-γ和poly（I：C）的共刺激也显著增强了NHEK中针对单纯疱疹病毒1型的抗病毒活性。除了在体外的结果，免疫组织化学分析显示，IFN-γ阳性细胞周围疱疹囊泡。这些发现表明IFN-γ可能通过增强角质形成细胞中TLR 3的表达和功能而有助于对皮肤病毒感染的先天免疫应答。
Toll-like receptors (TLRs) recognize specific microbial products in the innate immune response. TLR3, a double-stranded RNA sensor, is thought to have an important role in viral infections, but the regulation of TLR3 expression and its function in keratinocytes are not fully understood. Here we show the Th1 cytokine IFN-gamma increased the TLR3 expression via STAT1 in cultured normal human epidermal keratinocytes (NHEKs). Co-stimulation with IFN-gamma and the TLR3 ligand poly (I:C) synergistically increased the expression of IFN-beta, IL-6, IL-8, and human beta-defensin-2 in NHEKs compared with poly (I:C) or IFN-gamma alone. These synergistic inductions were significantly inhibited by an endosomal acidification inhibitor, chloroquine, and by TLR3 siRNA. Co-stimulation with IFN-gamma and poly (I:C) also significantly enhanced the anti-viral activity against herpes simplex virus type-1 in NHEKs compared with poly (I:C) or IFN-gamma alone. In addition to the in vitro findings, an immunohistochemical analysis revealed IFN-gamma positive cells surrounding herpetic vesicles. These findings indicate that IFN-gamma might contribute to the innate immune response to cutaneous viral infections by enhancing TLR3 expression and function in keratinocytes.