ID: 36. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Garg, Abhishek; Amatya, Nilesh; Chen, Kong; Agustin Cruz, J.; Grover, Prerna; Whibley, Natasha; Conti, Heather R.; Mir, Gerard Hernandez; Sirakova, Tatiana; Childs, Erin C.; Smithgall, Thomas E.; Biswas, Partha S.; Kolls, Jay K.; McGeachy, Mandy J.; Kolattukudy, Pappachan E.; Gaffen, Sarah L.
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 70
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.066
• Languages: English
• ISSNs: 1043-4666

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p id="sp005">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 <italic>Zc3h12a</italic> (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 <italic>Il6</italic>. Since IL-17 and TLR pathways share multiple target genes including <italic>Il6</italic>, 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's RNase activity, but not its deubiquitinase activity. <italic>In vivo</italic>, 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+/− mice was dramatically exacerbated during EAE and pulmonary inflammation. <italic>In vitro</italic>, MCPIP1 strongly inhibited the Lcn2 promoter activation by regulating the mRNA stability of the I<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qj5" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e251" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">κ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>B<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7kzq" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e256" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">ζ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> transcription factor. Unexpectedly, MCPIP1 also degraded <italic>Il17ra</italic> and <italic>Il17rc</italic> mRNA, independently of the 3' UTR. The cumulative impact of MCPIP1 on IL-6, I<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7qj5" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e267" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">κ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>B<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7kzq" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e272" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">ζ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.</p> </sec> </abstract>