Nuclear factor κB (NF-κB) activation primes cells to a pro-inflammatory polarized response to a Toll-like receptor 7 (TLR7) agonist
Nuclear factor κB (NF-κB) activation primes cells to a pro-inflammatory polarized response to a Toll-like receptor 7 (TLR7) agonist
复制标题
核因子 kappaB (NF-kappaB) 激活使细胞对 Toll 样受体 7 (TLR7) 激动剂产生促炎极化反应。
DOI：
10.1042/bj20090013
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发表时间：
2009-07-15
影响因子：
4.1
通讯作者：
Chuang, Tsung-Hsien
中科院分区：
文献类型：
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作者：
Lee, Jongdae;Hayashi, Masaaki;Chuang, Tsung-Hsien
TLR7 （toll样受体7）通过识别单链RNA病毒介导抗病毒免疫。小分子TLR7激动剂已被批准或正在评估中，用于治疗癌症或感染性疾病。虽然TLR7主要在有限的免疫细胞类型中表达，包括pDCs（浆细胞样树突状细胞），但在某些情况下，它也在非天然表达细胞（如肝细胞）中表达。为了阐明在这些非天然表达TLR7的细胞类型中，促炎刺激诱导TLR7和随后的细胞反应的分子基础，我们首先克隆并表征了TLR7的5'-启动子区域。该启动子的近端区域驱动TLR7基因的转录。促炎刺激通过该区域的NF-kappaB（核因子kappaB）结合基序激活tlr7转录，这种激活可以通过NF-kappaB结合位点突变或添加NF-kappaB抑制剂来阻断。进一步的研究表明，用tnf - α（肿瘤坏死因子- α）或IL-1（白细胞介素-1）预处理Hep3B肝细胞，使其对TLR7激动剂激活有反应。然而，与pDCs中的TLR7激活不同，pDCs对Th1极化的细胞因子产生刺激反应，肝细胞中促炎信号诱导TLR7重建nf - kappab依赖级联，而不是干扰素调节因子7依赖级联，导致促炎极化反应而不是Th1极化反应。这些结果表明，炎症刺激能够引发细胞对TLR7激动剂产生不同于天然表达TLR7细胞的免疫反应。
TLR7 (Toll-like receptor 7) mediates anti-viral immunity by recognizing ssRNA (single-stranded RNA) viruses. Small-molecular-mass TLR7 agonists have been approved, or are being evaluated, for treatment of cancers or infectious diseases. Although TLR7 is predominantly expressed in a restricted set of immune cell types, including pDCs (plasmacytoid dendritic cells), it is also expressed in non-native expressing cells (e.g. hepatocytes) under certain circumstances. To elucidate the molecular basis of TLR7 induction by pro-inflammatory stimulation and the subsequent cellular responses in these non-native TLR7-expressing cell types, we first cloned and characterized the 5'-promoter region of TLR7. The proximal region of this promoter drives the transcription of the TLR7 gene. Pro-inflammatory stimuli activated TLR 7 transcription via a NF-kappaB (nuclear factor kappaB)-binding motif in this region, and this activation could be blocked by mutation of the NF-kappaB binding site or addition of NF-kappaB inhibitors. Further studies showed that pretreatment of the Hep3B hepatocytes with TNF-alpha (tumour necrosis factor-alpha) or IL-1 (interleukin-1) rendered them responsive to TLR7 activation by a TLR7 agonist. However, distinct from TLR7 activation in pDCs, which respond to stimulation with Th1 polarized cytokine production, TLR7 induction by pro-inflammatory signals in hepatocytes reconstitutes the NF-kappaB-dependent cascade but not the IRF7 (interferon regulatory factor 7)-dependent cascade, resulting in a pro-inflammatory polarized response rather than a Th1 polarized response. These results indicate that inflammatory stimulation is capable of priming cells to respond to TLR7 agonist with an immune response that differs from that in native TLR7-expressing cells.