Am. J. Respir. Cell Mol. Biol., Volume 24, Number 1, January, 2001 58-65

Preferential Activation of Nuclear Factor of Activated T Cells c Correlates with Mouse Strain Susceptibility to Allergic Responses and Interleukin-4 Gene Expression

Judith Clancy Keen, Lynette Sholl, Marsha Wills-Karp, and Steve N. Georas

Departments of Medicine and Environmental Health Sciences, The Johns Hopkins University, Baltimore, Maryland

Dysregulated expression of the T helper 2 cytokine interleukin (IL)-4 is thought to play a fundamental role in the pathogenesis of allergic asthma. The molecular basis for dysregulated IL-4 production is not well understood. We analyzed in detail the molecular factors involved in regulating IL-4 transcription in a well-characterized mouse model. In this model, A/J mice developed allergen-induced IL-4 cytokine gene expression, airway inflammation, and hyperresponsiveness, whereas C3H/HeJ (C3H) mice did not. Here we report that isolated splenocytes from A/J and C3H mice stimulated ex vivo with concanavalin A reproduced the cytokine phenotype observed in the airway after antigen challenge. We hypothesized that differences in splenocyte IL-4 production involved either polymorphisms in regulatory IL-4 promoter regions, or the expression and activation of transcription factors necessary for promoter transactivation in a strain-dependent manner. To address these questions, we first sequenced ~ 700 base pairs containing well-characterized IL-4 promoter regulatory elements using genomic DNA obtained from C3H and A/J mice. Next, we used electrophoretic mobility shift assays with relevant IL-4 promoter sequences to screen nuclear extracts isolated from A/J and C3H splenocytes for functional transcriptional factor complexes. Here we show that susceptibility to antigen-induced airway hyperresponsiveness is not due to polymorphisms in the IL-4 promoter, but is associated with preferential expression of nuclear factor of activated T cells c in splenocyte nuclear extracts obtained from A/J mice. In conclusion, our data link dysregulated activation of a specific transcription factor with susceptibility to allergic airway inflammation.

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