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.


CONCLUSIONS
Different STAT6-dependent IL-4 functions require different thresholds of activated STAT6 molecules.
Burgis
Susanne
S
Institut fur Klinische Mikrobiologie, Immunologie und Hygiene, Universitat Erlangen-Nurnberg, Erlangen, Germany.
Gessner
André
A
D000818:Animals; D005260:Female; D018628:Gene Dosage; D006580:Genetic Carrier Screening; D007073:Immunoglobulin E / Q000096:biosynthesis; D015847:Interleukin-4 / Q000502:physiology*; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics*
D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D007073:Immunoglobulin E