Specific inhibition of interieukin-4-dependent Stat6 activation by an intracellularly delivered peptide

The transcription factor Stat6 (signal transducer and activator of transcri ption 6) is activated following stimulation with interleukin (IL)-4 or IL-1 3. Stat6 binds via a single SH2 domain first to tyrosine-phosphorylated mot ifs in the IL-4R alpha chain, and then to another Stat6 molecule, which res ults in the formation of active dimers. We show here that a peptide derived from the Stat6-binding region of IL-4R alpha (Stat6BP) is an effective inh ibitor when it is delivered into cells by coupling with a membrane-permeabl e peptide. Stat6BP completely inhibited EL-4 dependent phosphorylation of S tat6, as well as basal and IL-4 stimulated transcription from a reporter ge ne construct with a Stat6-dependent promoter, while IL-3 and IL-4 dependent phosphorylation of Stat5 was not affected. The inhibitory effect of Stat6B P was transient, but could be prolonged by treating the cells with the phos phatase inhibitor pervanadate.