IL-4/IL-13 signaling beyond JAK/STAT.
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-4Ralpha 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.
Jiang
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Department of Medicine and Microbiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Harris
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Rothman
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D002352:Carrier Proteins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018793:Interleukin-13 / Q000502:physiology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D053616:Janus Kinase 3; D016393:Lymphoma, B-Cell / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D018123:Receptors, Interleukin / Q000502:physiology; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000502:physiology; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology*
D002352:Carrier Proteins; C508181:IL13RA1 protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D047908:Intracellular Signaling Peptides and Proteins; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D010744:Phosphoric Monoester Hydrolases