IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages

• Published in: Free radical biology & medicine Vol. 54; pp. 1 - 16
• Main Authors: Bhattacharjee, Ashish, Shukla, Meenakshi, Yakubenko, Valentin P., Mulya, Anny, Kundu, Suman, Cathcart, Martha K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2013
• Subjects: Alternative activation; Arachidonate 15-Lipoxygenase - metabolism; Cells, Cultured; Cytokines; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Free radicals; Gene Expression Regulation; Gene regulation; Humans; Inflammation; Interleukin-13 - immunology; Interleukin-4 - immunology; Janus Kinase 1 - metabolism; Janus Kinase 2 - metabolism; Macrophage Activation - immunology; Macrophages - immunology; Monoamine Oxidase - metabolism; Monocytes; Monocytes - immunology; Reactive Oxygen Species - metabolism; Receptors, Interleukin-13 - metabolism; Receptors, Interleukin-4 - metabolism; ROS; Signal Transduction - immunology; STAT Transcription Factors - metabolism; Tissue Inhibitor of Metalloproteinase-3 - genetics; Tissue Inhibitor of Metalloproteinase-3 - metabolism; TYK2 Kinase - metabolism; Monocytes; Free radicals; Cytokines; Gene regulation; ROS; Inflammation; Alternative activation
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.10.553

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. [Display omitted] ► Distinct Jak/Stat pathways regulate gene expression in alternatively activated monocytes. ► IL-13 and IL-4 uniquely affect expression of particular genes such as DUSP1 and TIMP3. ► IL-4 and IL-13 activate different Jaks, which are upstream of several Stats. ► MAO-A expression/activity is required for tyramine-induced ROS generation. ► Different Jaks control MAO-A-mediated ROS in IL-4- and IL-13-activated monocytes.