Interleukin-4-induced STAT6 Recognizes and Activates a Target Site in the Promoter of the Interleukin-4 Receptor Gene

Abstract

Cytokines function as protein mediators that play a critical role in host defense and serve as a communication link between cells of native and acquired immunity. Cells respond to cytokines with specific biological changes that are dependent on the activation of new gene expression. Studies of the mechanism by which signals are mediated from the receptor to the nucleus by the interferon cytokines have revealed the activation by tyrosine phosphorylation of latent cytoplasmic transcription factors that subsequently translocate to the nucleus (1-4). This pathway has served as a model for signal transmission by many other cytokines including interleukin-4 (IL-4).

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

“…Stat6 has been proposed to regulate IL-4R expression, since a heterologous IL-4R promoter/luciferase reporter containing an endogenous Stat6 consensus binding sequence was activated by IL-4 in Stat6 overexpressing HeLa cells (Kotanides and Reich, 1996). In Stat6 7/7 ®broblasts, we observed that IL-4R basal expression and activation by IL-4 were not a ected by the loss of Stat6.…”

“…IL-4R expression in lymphocytes has been shown to be regulated by IL-4 treatment (Ohara and Paul, 1988) and a heterologous IL-4R promoter/reporter has also been shown to be enhanced through Stat6 (Kotanides and Reich, 1996). To test the role of Stat6 in ®broblast IL-4R modulation, we ®rst examined the competence of wild-type and Stat6 7/7 primary ®broblasts to respond to IL-4.…”

Anti-sense oligonucleotide of p21(waf1/cip1) prevents Interleukin 4-mediated elevation of p27(kip1) in low grade astrocytoma cells

“…Stimulation with IL-4 activates Jak tyrosine kinases to phosphorylate STAT6, after which STAT6 undergoes homodimerization and translocates to the nucleus (Damell, 1997;Takeda et al, 1997). STAT6 binding sites have been found in promoter regions of several IL-4-inducible genes (Kotanides and Reich, 1996;Lu et al, 1997). Binding sites for STAT1, another member of the STAT family, have been detected within the p21(waf1/cip1) promoter region, and activation of STAT1 and p21(waf1/cip1) are linked in some cells growth-arrested by EGF or ®broblast growth factor (Chin et al, 1996;Johnson et al, 1998).…”

The biology of Stat4 and Stat6

“…None of the other STAT proteins tested are capable of recognizing the N4 site in vitro (Mikita et al, 1996). Indeed, most of the Stat6 binding sites mapped in IL-4 responsive promoters have consisted of N4 sites (Delphin and Stavnezer, 1995;Kotanides and Reich, 1996). Therefore, Stat6 is able to selectively regulate IL-4 signal transduction not only by speci®cally interacting with the IL-4 receptor but also by recognizing a unique subset of STAT binding sites.…”