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

Free Radic Biol Med. 2013 Jan;54:1-16. doi: 10.1016/j.freeradbiomed.2012.10.553. Epub 2012 Nov 1.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arachidonate 15-Lipoxygenase / metabolism
  • Cells, Cultured
  • Dual Specificity Phosphatase 1 / genetics
  • Dual Specificity Phosphatase 1 / metabolism
  • Gene Expression Regulation
  • Humans
  • Interleukin-13 / immunology*
  • Interleukin-4 / immunology*
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / metabolism
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Monoamine Oxidase / metabolism
  • Monocytes / immunology*
  • Reactive Oxygen Species / metabolism
  • Receptors, Interleukin-13 / metabolism
  • Receptors, Interleukin-4 / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction / immunology
  • TYK2 Kinase / metabolism
  • Tissue Inhibitor of Metalloproteinase-3 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism


  • Interleukin-13
  • Reactive Oxygen Species
  • Receptors, Interleukin-13
  • Receptors, Interleukin-4
  • STAT Transcription Factors
  • Tissue Inhibitor of Metalloproteinase-3
  • Interleukin-4
  • Arachidonate 15-Lipoxygenase
  • Monoamine Oxidase
  • Janus Kinase 1
  • Janus Kinase 2
  • TYK2 Kinase
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1