前沿：可溶性白细胞介素-6受体由活化的CD4 T细胞中白细胞介素-6受体胞外域脱落产生。
Cutting edge: soluble IL-6R is produced by IL-6R ectodomain shedding in activated CD4 T cells.
作者信息
Briso Eva M, Dienz Oliver, Rincon Mercedes
机构信息
Department of Medicine/Immunobiology Program, University of Vermont, Burlington VT 05405, USA.
出版信息
J Immunol. 2008 Jun 1;180(11):7102-6. doi: 10.4049/jimmunol.180.11.7102.
Abstract
IL-6 trans-signaling via the soluble IL-6R (sIL-6R) plays an important role in the progression of several autoimmune diseases and cancer by providing IL-6-responsiveness to cells lacking IL-6R. However, the potential sources of sIL-6R are less understood. In this study we show that sIL-6R is produced by both naive and memory CD4 T cells upon TCR activation. The production of sIL-6R by activated CD4 T cells is mediated by shedding of the membrane-bound IL-6R, and this process correlates with the expression of the metalloproteinase ADAM17 in these cells. In contrast to CD4 T cells, CD8 T cells do not express ADAM17 and their production of sIL-6R is negligible. Thus, during an immune response CD4 T cells are an important source of sIL-6R. Production of sIL-6R by autoreactive CD4 T cells may contribute to their role in the development of autoimmune disease by conferring IL-6-responsiveness to cells lacking IL-6R such as synoviocytes.
摘要
通过可溶性白细胞介素-6受体（sIL-6R）进行的白细胞介素-6反式信号传导，通过赋予缺乏白细胞介素-6受体的细胞对白细胞介素-6的反应性，在几种自身免疫性疾病和癌症的进展中发挥重要作用。然而，sIL-6R的潜在来源尚不太清楚。在本研究中，我们表明sIL-6R在TCR激活后由初始和记忆性CD4 T细胞产生。活化的CD4 T细胞产生sIL-6R是由膜结合白细胞介素-6受体的脱落介导的，并且这个过程与这些细胞中金属蛋白酶ADAM17的表达相关。与CD4 T细胞相反，CD8 T细胞不表达ADAM17，它们产生sIL-6R的量可以忽略不计。因此，在免疫反应期间，CD4 T细胞是sIL-6R的重要来源。自身反应性CD4 T细胞产生sIL-6R可能通过赋予缺乏白细胞介素-6受体的细胞（如滑膜细胞）对白细胞介素-6的反应性，从而在自身免疫性疾病的发展中发挥作用。
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本文引用的文献
1
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Nat Immunol. 2007 Sep;8(9):942-9. doi: 10.1038/ni1496. Epub 2007 Aug 5.
2
Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells.前沿：通过可溶性IL-6R的转信号传导消除了初始CD4+CD25 T细胞中FoxP3的诱导。
J Immunol. 2007 Aug 15;179(4):2041-5. doi: 10.4049/jimmunol.179.4.2041.
3
Non-cell autonomous expression of TNF-alpha-converting enzyme ADAM17 is required for normal lymphocyte development.肿瘤坏死因子-α转化酶ADAM17的非细胞自主表达是正常淋巴细胞发育所必需的。
J Immunol. 2007 Apr 1;178(7):4214-21. doi: 10.4049/jimmunol.178.7.4214.
4
Interleukin-6 and its receptor: from bench to bedside.白细胞介素-6及其受体：从实验室到临床
Med Microbiol Immunol. 2006 Dec;195(4):173-83. doi: 10.1007/s00430-006-0019-9. Epub 2006 May 31.
5
Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer.白细胞介素-6的生物学功能由膜结合型和可溶性受体共同协调：在炎症和癌症中的作用
J Leukoc Biol. 2006 Aug;80(2):227-36. doi: 10.1189/jlb.1105674. Epub 2006 May 17.
6
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Int J Cancer. 2006 Aug 15;119(4):823-30. doi: 10.1002/ijc.21918.
7
The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.白细胞介素-6受体α链在体内变应性气道炎症期间控制肺CD4+CD25+调节性T细胞的发育和功能。
J Clin Invest. 2005 Feb;115(2):313-25. doi: 10.1172/JCI22433.
8
TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.转化生长因子-β通过抑制白细胞介素-6转信号传导来抑制结肠癌的肿瘤进展。
Immunity. 2004 Oct;21(4):491-501. doi: 10.1016/j.immuni.2004.07.020.
9
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Am J Pathol. 2004 Aug;165(2):471-80. doi: 10.1016/S0002-9440(10)63312-3.
10
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Eur J Biochem. 2004 Jun;271(12):2539-47. doi: 10.1111/j.1432-1033.2004.04184.x.
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