title: The Interleukin-13 Receptor-α1 Chain Is Essential for Induction of the Alternative Macrophage Activation Pathway by IL-13 but Not IL-4.
abstract: Macrophages coexpress both the interleukin (IL)-2Rγ chain (γ(c)) and IL-13Rα1. These receptor chains can heterodimerize with IL-4Rα to form type I or type II IL-4 receptor complexes, respectively. We used macrophages derived from Il2rg and Il13ra1 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 γ(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 γ(c) KO macrophages, it was not abolished, indicating that IL-4 can still signal through type II IL-4 receptors via the IL-13Rα1 chain. IL-13 failed to activate STAT6 in macrophages derived from Il13ra1 KO mice; however, these cells remained fully responsive to IL-4. The inability of IL-13 but not IL-4 to signal in Il13ra1(-/-) macrophages correlated with the inability of IL-13 but not IL-4 to induce expression of genes such as Arg1, Retnla and Ccl11 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 Il13ra1 KO macrophages. These findings demonstrate that the IL-13Rα1 chain is essential for induction of the AMA pathway by IL-13 but not IL-4.
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md., USA.
authors.forename: Faruk
authors.initials: F
authors.lastname: Sheikh
authors.forename: Harold
authors.initials: H
authors.lastname: Dickensheets
authors.forename: Joao
authors.initials: J
authors.lastname: Pedras-Vasconcelos
authors.forename: Thirumalai
authors.initials: T
authors.lastname: Ramalingam
authors.forename: Laura
authors.initials: L
authors.lastname: Helming
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D018845:CD11 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003170:Complement Pathway, Alternative / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D008561:Membrane Fusion / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor / Q000378:metabolism
chemical_list: D018845:CD11 Antigens; C507942:Il2rg protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053631:Interleukin Receptor Common gamma Subunit; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; C413576:Retnla protein, mouse; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; C544448:Arg1 protein, mouse; D001119:Arginase