ID: 36: MCPIP1/Regnase-1 is a negative feedback inhibitor regulating IL-17 signaling and inflammation

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• 作者：Abhishek Garg¹ ; ; Nilesh Amatya¹ ; Kong Chen² ; J. Agustin Cruz¹ ; Prerna Grover³ ; Natasha Whibley¹ ; Heather R. Conti¹ ; Gerard Hernandez Mir¹ ; Tatiana Sirakova⁴ ; Erin C. Childs¹ ; Thomas E. Smithgall³ ; Partha S. Biswas¹ ; Jay K. Kolls² ; Mandy J. McGeachy¹ ; Pappachan E. Kolattukudy⁴ ; Sarah L. Gaffen¹
• 刊名：Cytokine
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：76
• 期：1
• 页码：70
• 全文大小：44 K

文摘

IL-17A (IL-17) is a proinflammatory cytokine that mediates host defense against extracellular pathogens but also contributes to the pathogenesis of various autoimmune diseases. Despite advances in our understanding of IL-17 signal transduction mechanisms, it is far less clear how IL-17R activity is kept in check to prevent harmful bystander inflammation. In an effort to identify novel, physiologically relevant regulators of IL-17 signal transduction, we evaluated microarray data of IL-17RA-dependent genes that mediate antifungal immunity. We thus identified the gene m>Zc3h12am> (encoding MCPIP1/Regnase-1) as a possible feedback restriction element. MCPIP1 is an endoribonuclease (RNase) that inhibits TLR signaling in part by degrading cytokine mRNA transcripts such as m>Il6m>. Since IL-17 and TLR pathways share multiple target genes including m>Il6m>, we investigated the role of MCPIP1 in IL-17 signal transduction. Here, we demonstrate that MCPIP1 is upregulated by IL-17 and serves as a potent feedback inhibitor of IL-17 signal transduction. IL-17 signaling inhibition required MCPIP1&rsquo;s RNase activity, but not its deubiquitinase activity. m>In vivom>, resistance to disseminated Candida albicans infection was enhanced in MCPIP1 haploinsufficient mice; resistance was reversed in an IL-17R-deficient background. Conversely, IL-17-dependent pathology in MCPIP1+/&minus; mice was dramatically exacerbated during EAE and pulmonary inflammation. m>In vitro  m>, MCPIP1 strongly inhibited the Lcn2 promoter activation by regulating the mRNA stability of the Immlsi1" class="mathmlsrc">rmulatext stixSupport mathImg" data-mathURL="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S1043466615003324&_mathId=si1.gif&_user=111111111&_pii=S1043466615003324&_rdoc=1&_issn=10434666&md5=40a8bf019f9726b35d885131ce869aa8" title="Click to view the MathML source">魏mathContainer hidden">mathCode"><math altimg="si1.gif" overflow="scroll"><mrow><mi mathvariant="normal">魏mi>mrow>math>Bmmlsi2" class="mathmlsrc">rmulatext stixSupport mathImg" data-mathURL="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S1043466615003324&_mathId=si2.gif&_user=111111111&_pii=S1043466615003324&_rdoc=1&_issn=10434666&md5=da7a280d476052bbade49728d6a880d7" title="Click to view the MathML source">味mathContainer hidden">mathCode"><math altimg="si2.gif" overflow="scroll"><mrow><mi mathvariant="normal">味mi>mrow>math> transcription factor. Unexpectedly, MCPIP1 also degraded m>Il17ram> and m>Il17rc  m> mRNA, independently of the 3&rsquo; UTR. The cumulative impact of MCPIP1 on IL-6, Immlsi1" class="mathmlsrc">rmulatext stixSupport mathImg" data-mathURL="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S1043466615003324&_mathId=si1.gif&_user=111111111&_pii=S1043466615003324&_rdoc=1&_issn=10434666&md5=40a8bf019f9726b35d885131ce869aa8" title="Click to view the MathML source">魏mathContainer hidden">mathCode"><math altimg="si1.gif" overflow="scroll"><mrow><mi mathvariant="normal">魏mi>mrow>math>Bmmlsi2" class="mathmlsrc">rmulatext stixSupport mathImg" data-mathURL="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S1043466615003324&_mathId=si2.gif&_user=111111111&_pii=S1043466615003324&_rdoc=1&_issn=10434666&md5=da7a280d476052bbade49728d6a880d7" title="Click to view the MathML source">味mathContainer hidden">mathCode"><math altimg="si2.gif" overflow="scroll"><mrow><mi mathvariant="normal">味mi>mrow>math> and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.