Regulation of interleukin 4-mediated signaling by naturally occurring dominant negative and attenuated forms of human Stat6

Interleukin (IL)-4-mediated nuclear signaling by Stat6 has been implicated in lymphoid cell proliferation and the transcriptional activation of genes encoding major histocompatability complex (MHC) class II molecules and Fc receptors. To investigate IL-4-mediated transcriptional events, we cloned two naturally occurring human Stat6 isoforms, Stat6b and Stat6c, that encoded an NH(2)-terminal truncation or an SH2 domain deletion, respectively. Stat6 variant mRNAs were differentially expressed in many human tissues. To elucidate the biologic role of each isoform, we examined the consequences of overexpression in IL-4-responsive FDC-P2 cells. Stat6 and Stat6b (to a lesser extent) enhanced DNA synthesis, up-regulated endogenous MHC class II and Fcγ receptors, and became tyrosine phosphorylated in response to IL-4 stimulation. In contrast, Stat6c, which lacks functionally critical SH2 domain residues, unexpectedly inhibited IL-4-mediated mitogenesis and cell surface antigen expression and was not tyrosine phosphorylated. Although Stat6c only modestly diminished endogenous Stat6 tyrosine phosphorylation, it abolished endogenous Stat6 FcγRI and Iɛ DNA binding activity and FcγRI–luciferase reporter transcriptional activation. Our results indicate that the molecular mechanism of inhibition by Stat6c was due to suppression of endogenous Stat6 dimer formation. Thus, Stat6b and Stat6c are naturally occurring attenuated and dominant negative Stat6 variants, respectively, that affect IL-4-mediated biologic responses through differential transcriptional regulation.