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IL-4/IL-13 signaling beyond JAK/STAT

2000; Elsevier BV; Volume: 105; Issue: 6 Linguagem: Inglês

10.1067/mai.2000.107604

1097-6825

Hong Jiang, Miera B. Harris, Paul B. Rothman,

Toxin Mechanisms and Immunotoxins

Abstract In the past several years, extensive studies on the mechanisms underlying IL-4 and IL-13 signaling have enabled us to gain insight into how these cytokines regulate immune responses. Because both IL-4 and IL-13 use the IL-4Rα as a receptor component, these cytokines activate many common signaling pathways. Both of these cytokines use Janus kinases (JAKs) to initiate signaling and activate signal transducer and activator of transcription-6 (STAT6), which is a transcription factor required for many of their biologic functions. In addition to JAK/STAT, these cytokines also activate a variety of other signaling molecules that are important in regulating IL-4–induced proliferation and protection from apoptosis. Suppressor of cytokine signaling-1 (SOCS-1) is a molecule that can inhibit the activation of IL-4 signaling through the inhibition of JAKs. The Fes tyrosine kinase is activated by IL-4 and appears to be important in regulating IL-4–induced proliferation through the phosphorylation of insulin receptor substrate (IRS) molecules. IRS molecules are essential for IL-4–induced proliferation through their ability to recruit phosphoinositol-3 kinase to the activated IL-4 receptor kinase. In addition, IL-4 can activate a number of phosphatases including SH2-containing inositol phosphatase (SHIP), SHP-1, and SHP-2. Finally, B-cell lymphoma gene-6 (BCL-6) appears to regulate a subset of IL-4–induced genes. Thus the biologic responses induced by IL-4/IL-13 require a complex interaction of signaling pathways and regulators. (J Allergy Clin Immunol 2000;105:1063-70.)