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

In the past several years, extensive studies on the mechanisms underlying I L-4 and IL-13 signaling have enabled us to gain insight into how these cyto kines regulate immune responses. Because both IL-4 and IL-13 use the IL-4R alpha as a receptor component, these cytokines activate many common signali ng pathways. Both of these cytokines use Janus kinases (JAKs) to initiate s ignaling and activate signal transducer and activator of transcription-6 (S TAT6), 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 signal ing-1 (SOCS-1) is a molecule that can inhibit the activation of IL-4 signal ing 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 ab ility to recruit phosphoinositol-3 kinase to the activated IL-4 receptor ki nase, 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 intera ction of signaling pathways and regulators.