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J.Immunol.:自身免疫病相关新药物作用靶点GPCR

2013-05-06 上海药物研究所 上海药物研究所

G蛋白偶联受体(GPCR)是一类重要的药物作用靶点,目前市场上有超过40%的药物是通过作用于GPCR起到治疗作用。人体大约有800-1000个GPCR,发现GPCR在重大疾病中的新作用可以为疾病治疗提供新药靶或新方法。 多发性硬化(Multiple sclerosis,MS)是一种与神经系统相关的自身免疫性疾病,是仅次于创伤的中青年人致残原因,目前尚缺乏有效的治疗药物,有着“死不了的癌症”之称。

G蛋白偶联受体(GPCR)是一类重要的药物作用靶点,目前市场上有超过40%的药物是通过作用于GPCR起到治疗作用。人体大约有800-1000个GPCR,发现GPCR在重大疾病中的新作用可以为疾病治疗提供新药靶或新方法。

多发性硬化(Multiple sclerosis,MS)是一种与神经系统相关的自身免疫性疾病,是仅次于创伤的中青年人致残原因,目前尚缺乏有效的治疗药物,有着“死不了的癌症”之称。同济大学博士生魏巍、副教授杜昌升等在研究GPCR与该疾病关系时发现,有一类GPCR(A2B腺苷受体,A2BAR)在MS的动物模型EAE小鼠上随疾病进程表达显着提高。A2BAR与其配体腺苷的结合能力较弱,一般需要高浓度的腺苷才激活。而在炎症、缺氧等应激状态,体内腺苷水平会极大提高而激活A2BAR。

利用A2BAR敲除小鼠及A2BAR特异性拮抗剂,研究发现阻断A2BAR的信号转导可以有效抑制疾病的进程。进一步研究发现,位于抗原递呈的树突状细胞(DC)表面的A2BAR对炎性因子IL-6的分泌至关重要,抑制A2BAR刺激的IL-6分泌可以有效抑制下游T效应细胞的分化,从而缓解疾病的发生。机制研究发现,A2BAR主要是通过激活PLC-PKC及p38 MAPK两条通路来刺激IL-6分泌的。更有趣的是,在MS病人血细胞中,A2BAR也是上调的,进一步提示其与疾病的相关性。

本研究提示,A2BAR可作为自身免疫性疾病药物开发的新靶点,研究成果于12月5日在线发表于Journal of Immunology。

本研究工作是在谢欣研究员指导下完成。谢欣研究员是中科院上海药物研究所课题组长,国家新药筛选中心副主任,同济大学生命科学与技术学院兼职教授,博士生导师。主要从事基于GPCR的新药发现及机制研究,以及小分子化合物调控干细胞命运的研究。研究组在不久前报道了靶向半胱氨酸白三烯受体的抗哮喘药物可用于治疗MS (Journal of Immunology. 2011;187(5):2336-45)。本研究工作中的MS病人样品由华山医院的吴志英教授团队采集提供。

本研究工作得到国家自然科学基金委、科技部以及上海市科委项目的支持

doi:10.4049/jimmunol.1103721
PMC:
PMID:

Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation

Wei Wei,*,†,1 Changsheng Du,*,1 Jie Lv,*,† Guixian Zhao,‡,x Zhenxin Li,‡,x Zhiying Wu,‡,x Gyo¨rgy Hasko´,{ and Xin Xie*,†

Adenosine is a key endogenous signaling molecule that regulates immune responses. A2B adenosine receptor (AR) is a relatively low-affinity receptor for adenosine, and the activation of A2BAR is believed to require pathological level of adenosine that is associated with ischemia, inflammation, trauma, or other types of stress. The role of A2BAR in the pathogenesis of multiple sclerosis (MS) is still unclear. In this study, we discovered that A2BAR was upregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of experimental autoimmune encephalomyelitis (EAE) mice. A2BAR-specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the CNS from immune damage. A2BAR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A2BAR inhibited Th17 cell differentiation by blocking IL-6 production from APCs such as dendritic cells. In dendritic cells, A2BAR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A2BAR significantly reduced adenosine-mediated IL-6 production. The phospholipase Cb–protein kinase C and p38 MAPK pathways were found to be involved in the A2BAR-mediated IL- 6 production. Our findings not only revealed the pathological role of A2BAR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs.

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    2013-07-26 马龙
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  5. [GetPortalCommentsPageByObjectIdResponse(id=2041770, encodeId=e95a2041e70d2, content=<a href='/topic/show?id=96372910100' target=_blank style='color:#2F92EE;'>#免疫病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=29101, encryptionId=96372910100, topicName=免疫病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=21015, createdName=heli0118, createdTime=Mon Apr 21 07:56:00 CST 2014, time=2014-04-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1658642, encodeId=88cc1658642aa, content=<a href='/topic/show?id=95d0819851' target=_blank style='color:#2F92EE;'>#GPCR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=105, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8198, encryptionId=95d0819851, topicName=GPCR)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=646024894629, createdName=马龙, createdTime=Fri Jul 26 09:56:00 CST 2013, time=2013-07-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1923566, encodeId=b96f192356641, content=<a href='/topic/show?id=f9f25864447' target=_blank style='color:#2F92EE;'>#新药物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58644, encryptionId=f9f25864447, topicName=新药物)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIuNQXObUwZmFG3VcZa2uhFq27sY7vfTowUhQCgRj2bj1odUibMF4sFXpuRLf6IE5t5yGVDSiaOoOcQ/132, createdBy=1e622500088, createdName=ms1065684921169360, createdTime=Sun Mar 09 15:56:00 CST 2014, time=2014-03-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1971509, encodeId=a02f19e1509f0, content=<a href='/topic/show?id=49ac8e66616' target=_blank style='color:#2F92EE;'>#药物作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87666, encryptionId=49ac8e66616, topicName=药物作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ba58436, createdName=马龙, createdTime=Mon Sep 23 04:56:00 CST 2013, time=2013-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1291725, encodeId=b6061291e251a, content=<a href='/topic/show?id=62f68635461' target=_blank style='color:#2F92EE;'>#自身免疫病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=86354, encryptionId=62f68635461, topicName=自身免疫病)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ac1c235, createdName=tonychen21, createdTime=Wed May 08 14:56:00 CST 2013, time=2013-05-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1419357, encodeId=bae1141935e3f, content=<a href='/topic/show?id=e290138682e' target=_blank style='color:#2F92EE;'>#PCR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13868, encryptionId=e290138682e, topicName=PCR)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9cc43496966, createdName=Tommy1950, createdTime=Wed May 08 14:56:00 CST 2013, time=2013-05-08, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=2041770, encodeId=e95a2041e70d2, content=<a href='/topic/show?id=96372910100' target=_blank style='color:#2F92EE;'>#免疫病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=29101, encryptionId=96372910100, topicName=免疫病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=21015, createdName=heli0118, createdTime=Mon Apr 21 07:56:00 CST 2014, time=2014-04-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1658642, encodeId=88cc1658642aa, content=<a href='/topic/show?id=95d0819851' target=_blank style='color:#2F92EE;'>#GPCR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=105, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8198, encryptionId=95d0819851, topicName=GPCR)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=646024894629, createdName=马龙, createdTime=Fri Jul 26 09:56:00 CST 2013, time=2013-07-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1923566, encodeId=b96f192356641, content=<a href='/topic/show?id=f9f25864447' target=_blank style='color:#2F92EE;'>#新药物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58644, encryptionId=f9f25864447, topicName=新药物)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIuNQXObUwZmFG3VcZa2uhFq27sY7vfTowUhQCgRj2bj1odUibMF4sFXpuRLf6IE5t5yGVDSiaOoOcQ/132, createdBy=1e622500088, createdName=ms1065684921169360, createdTime=Sun Mar 09 15:56:00 CST 2014, time=2014-03-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1971509, encodeId=a02f19e1509f0, content=<a href='/topic/show?id=49ac8e66616' target=_blank style='color:#2F92EE;'>#药物作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87666, encryptionId=49ac8e66616, topicName=药物作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ba58436, createdName=马龙, createdTime=Mon Sep 23 04:56:00 CST 2013, time=2013-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1291725, encodeId=b6061291e251a, content=<a href='/topic/show?id=62f68635461' target=_blank style='color:#2F92EE;'>#自身免疫病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=86354, encryptionId=62f68635461, topicName=自身免疫病)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ac1c235, createdName=tonychen21, createdTime=Wed May 08 14:56:00 CST 2013, time=2013-05-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1419357, encodeId=bae1141935e3f, content=<a href='/topic/show?id=e290138682e' target=_blank style='color:#2F92EE;'>#PCR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13868, encryptionId=e290138682e, topicName=PCR)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9cc43496966, createdName=Tommy1950, createdTime=Wed May 08 14:56:00 CST 2013, time=2013-05-08, status=1, ipAttribution=)]
    2013-05-08 Tommy1950
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