Unexpected Phenotype of STAT6 Heterozygous Mice Implies Distinct STAT6 Dosage Requirements for Different IL-4 Functions

BACKGROUND: STAT6 is an important transcription factor in interleukin-4 (IL-4) signaling, a key cytokine in atopic diseases and allergic asthma. STAT6 gene-targeted mice are unable to develop IgE and T helper 2 cell (Th2) responses in several models of allergic and infectious diseases. In experiments to further elucidate STAT6 functions in vivo, we unexpectedly observed severely impaired IL-4 functions in STAT6 heterozygous (STAT6+/-) mice which were further analyzed in this study. METHODS: BALB/c mice, either wild-type (STAT6+/+), STAT6 heterozygous (STAT6+/-) or STAT6 deficient (STAT6-/-), were analyzed for their ability to mount an IL-4-induced IgE response in vitro and in vivo. Supernatants of stimulated B cells and sera of Leishmania major-infected mice were analyzed for IgE, IgG1 and IgG2a concentrations by ELISA. Transcripts accompanying IgE class switching were amplified by RT-PCR and the expression of CD23 and MHC class II molecules on B cells was assessed by FACS analysis. RESULTS: B cells from STAT6+/- mice were unable to secrete IgE in vitro and in vivo and transcripts accompanying IgE class switching were drastically reduced, whereas IL-4-induced upregulation of MHC class II was unimpaired and CD23 expression levels were only slightly affected. Additionally, STAT6+/- mice were equally resistant to infection with L. major as STAT6-deficient (STAT6-/-) mice, due to a defect in mounting a Th2-dominated immune response. CONCLUSION: Different STAT6-dependent IL-4 functions require different thresholds of activated STAT6 molecules.