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

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• 作者：Ashish Bhattacharjee^a ; ^b ; Meenakshi Shukla^a ; ^b ; Valentin P. Yakubenko^a ; ^b ; Anny Mulya^a ; ^b ; Suman Kundu^a ; ^b ; Martha K. Cathcart^a ; ^b ; ^{cathcam@ccf.org}
• 关键词：Monocytes ; Cytokines ; Inflammation ; Gene regulation ; ROS ; Alternative activation ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：54
• 期：Complete
• 页码：1-16
• 全文大小：2611 K

文摘

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-4R¦Á and IL-13R¦Á1), 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-4R¦Á/Jak2/Stat3 and IL-13R¦Á1/Tyk2/Stat1/Stat6 signaling pathways, IL-4 can use only the IL-4R¦Á/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.