可溶性白细胞介素6受体介导的DNA和RNA病毒天然免疫反应机制研究
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摘要
白细胞介素6受体,以膜受体和可溶性受体两种形式存在,在免疫反应中有着重要的作用。相比于在细胞中表达和定位极其有限的膜受体形式而言,可溶性受体因为能随体液转运而必然具有更深刻的生物学意义和更广泛的运用。白细胞介素6受体已被确认可以作为一种潜在的预防冠心病的治疗靶标。然而关于在病毒感染过程中自细胞介素6受体所发挥作用的研究报道还很少。在这样的背景下,本论文对可溶性的白细胞介素6受体(sIL6R)在病毒天然免疫反应机制中的作用进行了初步研究。
第一部分研究背景,介绍了白细胞介素6受体的最新研究进展,对环加氧酶2(COX-2)的表达调控机制和干扰素抗病毒的机制进行了综述。
第二部分是本文的主要研究内容,研究了可溶性白细胞介素6受体介导的对病毒天然免疫反应机制。
首先,我们证明病毒感染后通过COX-2通路诱导sIL6R表达,而不是诱导IL6表达,IL6也不能诱导sIL6R的表达。有趣的是,sIL6R表现出广谱的从DNA病毒到RNA病毒的抗病毒作用,包括乙型肝炎病毒、流感病毒、人肠道病毒71和水疱型口炎病毒。其次,我们发现在抗病毒作用中sIL6R和IL6没有协同效果,而且sIL6R与p28结合可以激活Ⅰ型干扰素通路并在一定程度上起到抗病毒效果。此外,sIL6R通过促进IRF3和NF-κB入核,诱导Ⅰ型干扰素产生,并激活Ⅰ型干扰素下游作用因子OAS,PKR,Mx。最后我们在临床水平验证细胞学水平的结论：发现在甲型流感和乙型肝炎病毒感染患者血清,外周血淋巴细胞和咽拭子中sIL6R都以高表达形式存在。因此,我们的研究结果证明了是sIL6R而不是IL6在宿主抗病毒反应中的起到的重要作用。
综上所述,本论文从信号通路、转录因子调控、抗病毒机制等方面研究了sIL6R独立于IL6的新生物学功能。sIL6R能促进细胞产生干扰素且激活下游通路而达到广谱抗病毒效果。这一新发现有利于阐明sIL6R在抗病毒反应中的作用,同时也为研制抗病毒药物提供理论基础。
The interleukin-6receptor, which exists as membrane-bound and soluble forms, plays critical roles in the immune response. Compare with limited expression and cell location of membrane-bound form, fluid transfer of souble form decided its more profound biological significance and wider application. The Interleukin-6receptor has been identified as a potential therapeutic target for preventing coronary heart disease. However, little is known about the role of this receptor during viral infection. Here we did preliminary research on the role of souble Interleukin-6receptor (sIL6R) in innate immune response to viruses.
Party1introduced the update of souble Interleukin-6receptor and reviewed regulation mechanism of cyclooxygenases-2(COX-2) and interferon antiviral mechanism.
Party2is the main research content of this article, describes the mechanism of souble Interleukin-6receptor-mediated innate immune response to viruses.
First, we show that sIL6R but not IL6is induced by viral infection via the cyclooxygenase-2pathway. sIL6R is not induced by IL6, neither. Interestingly, sIL6R but not IL6exhibited extensive antiviral activity to DNA and RNA viruses including hepatitis B virus, influenza virus, enterovirus-71, and vesicular stomatitis virus. Secondly, synergistic effects on antiviral action were not observed by combination of sIL6R and IL6. And sIL6R mediated antiviral responses partly via p28to active type
Ⅰ IFN pathway. Furthermore, sIL6R induced type I IFN by promoting IRF3and NF-κB nuclear translocation, which led to activation of type I IFN downstream effectors including OAS, PKR, and Mx. Final, we verify our cytological level conclusion in clinical samples. Results show that the high expression level of sIL6R in serum, peripheral blood mononuclear cell and throat swab from influenza virus or hepatitis B virus infected patients. Thus, our results demonstrate that sIL6R, but not IL6, plays an important role in the host antiviral response.
In conclusion, this thesis studied sIL6R had new biological function independent of IL6on the signal pathway, regulation of transcription factors and antivial mechanism. sIL6R could promote the immune cells to produce interferon and activate the downstream pathways to achieve broad-spectrum antiviral effect. This new find is helpful to clarify sIL6R's role in antiviral response, at the same time providing theoretical basis for development of antiviral drugs.
第一部分研究背景,介绍了白细胞介素6受体的最新研究进展,对环加氧酶2(COX-2)的表达调控机制和干扰素抗病毒的机制进行了综述。
第二部分是本文的主要研究内容,研究了可溶性白细胞介素6受体介导的对病毒天然免疫反应机制。
首先,我们证明病毒感染后通过COX-2通路诱导sIL6R表达,而不是诱导IL6表达,IL6也不能诱导sIL6R的表达。有趣的是,sIL6R表现出广谱的从DNA病毒到RNA病毒的抗病毒作用,包括乙型肝炎病毒、流感病毒、人肠道病毒71和水疱型口炎病毒。其次,我们发现在抗病毒作用中sIL6R和IL6没有协同效果,而且sIL6R与p28结合可以激活Ⅰ型干扰素通路并在一定程度上起到抗病毒效果。此外,sIL6R通过促进IRF3和NF-κB入核,诱导Ⅰ型干扰素产生,并激活Ⅰ型干扰素下游作用因子OAS,PKR,Mx。最后我们在临床水平验证细胞学水平的结论：发现在甲型流感和乙型肝炎病毒感染患者血清,外周血淋巴细胞和咽拭子中sIL6R都以高表达形式存在。因此,我们的研究结果证明了是sIL6R而不是IL6在宿主抗病毒反应中的起到的重要作用。
综上所述,本论文从信号通路、转录因子调控、抗病毒机制等方面研究了sIL6R独立于IL6的新生物学功能。sIL6R能促进细胞产生干扰素且激活下游通路而达到广谱抗病毒效果。这一新发现有利于阐明sIL6R在抗病毒反应中的作用,同时也为研制抗病毒药物提供理论基础。
The interleukin-6receptor, which exists as membrane-bound and soluble forms, plays critical roles in the immune response. Compare with limited expression and cell location of membrane-bound form, fluid transfer of souble form decided its more profound biological significance and wider application. The Interleukin-6receptor has been identified as a potential therapeutic target for preventing coronary heart disease. However, little is known about the role of this receptor during viral infection. Here we did preliminary research on the role of souble Interleukin-6receptor (sIL6R) in innate immune response to viruses.
Party1introduced the update of souble Interleukin-6receptor and reviewed regulation mechanism of cyclooxygenases-2(COX-2) and interferon antiviral mechanism.
Party2is the main research content of this article, describes the mechanism of souble Interleukin-6receptor-mediated innate immune response to viruses.
First, we show that sIL6R but not IL6is induced by viral infection via the cyclooxygenase-2pathway. sIL6R is not induced by IL6, neither. Interestingly, sIL6R but not IL6exhibited extensive antiviral activity to DNA and RNA viruses including hepatitis B virus, influenza virus, enterovirus-71, and vesicular stomatitis virus. Secondly, synergistic effects on antiviral action were not observed by combination of sIL6R and IL6. And sIL6R mediated antiviral responses partly via p28to active type
Ⅰ IFN pathway. Furthermore, sIL6R induced type I IFN by promoting IRF3and NF-κB nuclear translocation, which led to activation of type I IFN downstream effectors including OAS, PKR, and Mx. Final, we verify our cytological level conclusion in clinical samples. Results show that the high expression level of sIL6R in serum, peripheral blood mononuclear cell and throat swab from influenza virus or hepatitis B virus infected patients. Thus, our results demonstrate that sIL6R, but not IL6, plays an important role in the host antiviral response.
In conclusion, this thesis studied sIL6R had new biological function independent of IL6on the signal pathway, regulation of transcription factors and antivial mechanism. sIL6R could promote the immune cells to produce interferon and activate the downstream pathways to achieve broad-spectrum antiviral effect. This new find is helpful to clarify sIL6R's role in antiviral response, at the same time providing theoretical basis for development of antiviral drugs.
引文
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