An Interleukin-4-Induced Transcription Factor: IL-4 Stat

Abstract

Interleukin-4 (IL-4) is an immunomodulatory cytokine secreted by activated T lymphocytes, basophils, and mast cells. It plays an important role in modulating the balance of T helper (Th) cell subsets, favoring expansion of the Th2 lineage relative to Th1. Imbalance of these T lymphocyte subsets has been implicated in immunological diseases including allergy, inflammation, and autoimmune disease. IL-4 may mediate its biological effects, at least in part, by activating a tyrosine-phosphorylated DNA binding protein. This protein has now been purified and its encoding gene cloned. Examination of the primary amino acid sequence of this protein indicates that it is a member of the signal transducers and activators of transcription (Stat) family of DNA binding proteins, hereby designated IL-4 Stat. Study of the inhibitory activities of phosphotyrosine-containing peptides derived from the intracellular domain of the IL-4 receptor provided evidence for direct coupling of receptor and transcription factor during the IL-4 Stat activation cycle. Such observations indicate that IL-4 Stat has the same functional domain for both receptor coupling and dimerization.

IL-4 Induces Differentiation and Expansion of Th2 Cytokine-Producing Eosinophils

“…Activated JAK1 and JAK3 then phosphorylate tyrosine residues located in the cytoplasmic domain of the IL-4R␣ chain. The phosphorylated tyrosine residues then serve as docking sites to recruit STAT6 (10), which has been shown to enhance the expression of two key Th2-specific transcription factors, GATA3 and c-maf (11,12). When IL-4R␣ chain, STAT6, GATA3, or c-maf expression is disrupted, IL-4 fails to induce typical Th2 responses (13)(14)(15)(16).…”

The biology of Stat4 and Stat6

“…Additionally there was evidence that a latent cytoplasmic factor was tyrosine phosphorylated after IL-4 stimulation and subsequently redistributed to the nucleus. In order to clone the factor, an IL-4 responsive DNA element from the FcgRI promoter was used to purify this activity from protein extracts derived from an IL-4 treated cell line (Hou et al, 1994). The protein that bound to the site was tyrosine phosphorylated in response to IL-4 and shared homology with other known STAT proteins in its proposed DNA binding, SH3 and SH2 domains.…”

“…The protein that bound to the site was tyrosine phosphorylated in response to IL-4 and shared homology with other known STAT proteins in its proposed DNA binding, SH3 and SH2 domains. The protein was termed by several groups STF-IL-4, IL-4 STAT, IL-4 NAF and ultimately Stat6 (Hou et al, 1994;Kotanides and Reich, 1993;Quelle et al, 1995;Schindler et al, 1994).…”

“…This precise speci®city is controlled at two levels. First, the STAT proteins bind via their SH2 domains to speci®c docking sites on the corresponding activated cytokine receptor (Hou et al, 1994;Mikita et al, 1998a;Schindler et al, 1995). For example, Stat6 only recognizes phosphorylated tyrosines on the cytoplasmic tail of IL-4 receptor a chain and does not interact with the phospho-tyrosines on the IFNg receptor.…”

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

“…Each of these is activated by specific stimuli. STAT6 was originally identified as a gamma-activated sequence binding protein in extracts derived from interleukin (IL)-4-treated cell lines (Kotanides and Reich, 1993;Hou et al, 1994;Schindler et al, 1994). Accordingly, IL-4 can specifically induce tyrosine phosphorylation of STAT6.…”