title: IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages.
abstract: Monocytes/macrophages are innate immune cells that play a crucial role in the resolution of inflammation. In the presence of the Th2 cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13), they display an anti-inflammatory profile and this activation pathway is known as alternative activation. In this study we compare and differentiate pathways mediated by IL-4 and IL-13 activation of human monocytes/macrophages. Here we report differential regulation of IL-4 and IL-13 signaling in monocytes/macrophages starting from IL-4/IL-13 cytokine receptors to Jak/Stat-mediated signaling pathways that ultimately control expression of several inflammatory genes. Our data demonstrate that although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4Rα and IL-13Rα1), IL-4 stimulates Jak1 activation. We further show that Jak2 is upstream of Stat3 activation and Tyk2 controls Stat1 and Stat6 activation in response to IL-13 stimulation. In contrast, Jak1 regulates Stat3 and Stat6 activation in IL-4-induced monocytes. Our results further reveal that although IL-13 utilizes both IL-4Rα/Jak2/Stat3 and IL-13Rα1/Tyk2/Stat1/Stat6 signaling pathways, IL-4 can use only the IL-4Rα/Jak1/Stat3/Stat6 cascade to regulate the expression of some critical inflammatory genes, including 15-lipoxygenase, monoamine oxidase A (MAO-A), and the scavenger receptor CD36. Moreover, we demonstrate here that IL-13 and IL-4 can uniquely affect the expression of particular genes such as dual-specificity phosphatase 1 and tissue inhibitor of metalloprotease-3 and do so through different Jaks. As evidence of differential regulation of gene function by IL-4 and IL-13, we further report that MAO-A-mediated reactive oxygen species generation is influenced by different Jaks. Collectively, these results have major implications for understanding the mechanism and function of alternatively activated monocytes/macrophages by IL-4 and IL-13 and add novel insights into the pathogenesis and potential treatment of various inflammatory diseases.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Shukla
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.forename: Anny
authors.initials: A
authors.lastname: Mulya
authors.forename: Suman
authors.initials: S
authors.lastname: Kundu
authors.forename: Martha K
authors.initials: MK
authors.lastname: Cathcart
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008995:Monoamine Oxidase / Q000378:metabolism; D009000:Monocytes / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053660:Receptors, Interleukin-13 / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D053634:TYK2 Kinase / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D017382:Reactive Oxygen Species; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D050791:STAT Transcription Factors; D019717:Tissue Inhibitor of Metalloproteinase-3; D015847:Interleukin-4; D001093:Arachidonate 15-Lipoxygenase; D008995:Monoamine Oxidase; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1