ID: 193: ADAM10 controls a novel IL-11 trans-signalling pathway

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• 作者：Juliane Lokau¹ ; ; Maria Aghte¹ ; Georg H. Waetzig² ; Stefan Rose-John¹ ; Christoph Garbers¹
• 刊名：Cytokine
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：76
• 期：1
• 页码：99
• 全文大小：46 K

文摘

Interleukin (IL)-11 is a member of the IL-6 family which has been initially described to have anti-inflammatory properties. However, recent studies revealed that overshooting IL-11 activity is involved in inflammation and the progression of epithelial cancers. IL-11 binds to the membrane-bound IL-11 receptor (IL-11R), and this complex can then initiate signal transduction by recruiting two molecules of the hmlsrc">hImg" data-mathURL="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S1043466615004639&_mathId=si1.gif&_user=111111111&_pii=S1043466615004639&_rdoc=1&_issn=10434666&md5=d62d06e59ee4c2378dab2c55d3e55911" title="Click to view the MathML source">βhContainer hidden">hCode">h altimg="si1.gif" overflow="scroll">hvariant="normal">βh>-receptor glycoprotein (gp)130, which predominantly leads to activation of the JAK/STAT pathways. Gp130 is ubiquitously expressed, and IL-11R expression was found on several cell types including osteoblasts, osteoclasts, T cells and macrophages.

Proteolytic processing of cytokine receptors is an important regulatory element for their signalling capacity, which not only regulates the amount of the receptors on the cell surface, but also creates soluble receptors with distinct biological functions. Here, we show for the first time that the metalloprotease ADAM10, but not ADAM17, is able to cleave the IL-11R and release its ectodomain. Chimeric receptors of the IL-11R and the IL-6R revealed structural traits required for proteolytic processing and showed that a small part of the stalk region is responsible for ADAM17’s ability to discriminate between substrate and non-substrate. Furthermore, we show that a single amino acid mutation within the stalk is sufficient to generate a proteolysis-resistant IL-11R variant.

The generated soluble IL-11R binds IL-11, and the resulting complex can then bind to gp130 and thus activate cells even though they do not express the membrane-bound IL-11R. This novel IL-11 trans-signalling pathway can be specifically inhibited by the anti-inflammatory designer protein sgp130Fc.