ID: 43. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Donnelly, Raymond P.; Sheikh, Faruk; Dickensheets, Harold; Ramalingam, Thirumalai; Helming, Laura; Gordon, Siamon
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 72
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.073
• 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">Macrophages coexpress both the interleukin (IL)-2R-gamma chain (<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p5k" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e122" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>c) and IL-13R-alpha 1. These receptor chains can heterodimerize with IL-4R<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7pf0" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e127" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> to form type I or type II IL-4 receptor complexes, respectively. We used macrophages derived from <italic>Il2rg</italic> and <italic>Il13ra1</italic> knockout (KO) mice to evaluate the requirements for these receptor chains for induction of the alternative macrophage activation (AMA) pathway by IL-4 and IL-13. Absence of <inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p5k" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e138" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>c significantly decreased activation of STAT6 by IL-4 but not IL-13. However, although activation of STAT6 by IL-4 was markedly reduced in <italic>Il2rg</italic> KO macrophages, it was not abolished, indicating that IL-4 can still signal through type II IL-4 receptors via the IL-13R<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7pf0" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e147" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>1 chain. IL-13 failed to activate STAT6 in macrophages derived from <italic>Il13ra1</italic> KO mice; however, these cells remained fully responsive to IL-4. The inability of IL-13 but not IL-4 to signal in <italic>Il13ra1</italic>−/− macrophages correlated with the inability of IL-13 but not IL-4 to induce expression of genes such as <italic>Arg1</italic>, <italic>Retnla</italic> and <italic>Ccl11</italic> that are characteristically expressed by alternatively activated macrophages. In addition, IL-13 but not IL-4 failed to induce membrane fusion and giant cell formation by <italic>Il13ra1</italic> KO macrophages. These findings demonstrate that the IL-13R<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7pf0" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e171" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>1 chain is essential for induction of the AMA pathway by IL-13 but not IL-4. Furthermore, the IL-13R-alpha 1 chain represents an excellent target for development of neutralizing monoclonal antibodies to inhibit the pro-inflammatory activities of IL-13.</p> </sec> </abstract>