IL-4 and IL-5 Regulate the Allergic Response in NFAT1 Deficiency

Activation of allergen-specific CD4+ Th2 lymphocytes promotes the secretion of several cytokines, including IL-4, which induces IgE antibody synthesis, and IL-5, which leads to eosinophil recruitment. The production of these cytokines by Th2 cells is regulated by activation of transcription factors, such as NFAT proteins (nuclear factor of activated T cells), that influence the transcription of genes involved in allergy and eosinophil function.1 NFATs are expressed in T, B, mast, and natural killer (NK) cells. NFAT binding sites are in the promoter/enhancer regions of genes encoding IL-4 and IL-5 as well as other cytokines and cell surface receptors.1

Figure 1. A schematic representation demonstrating that allergen stimulation of NFAT1-deficient Th2 lymphocytes leads to increased production and secretion of the cytokines, IL-4 and IL-5. Overproduction of IL-4 and IL-5 heightens the allergic response by promoting the secretion of high levels of serum IgE and eosinophilia.

In an in vivo model of allergic inflammation, mice lacking the NFAT1 protein surprisingly had increased pleural accumulation of eosinophils, increased serum IgE levels and an abnormal pattern of IL-4 gene expression.2-3 Viola et al.4 showed that the NFAT1-deficient allergic phenotype, with eosinophilia associated with increased serum IgE levels, was associated with overexpression of IL-4 and IL-5. In response to allergen stimulation, overproduction of IL-4 and IL-5 led to an increased allergic response. The eosinophilia and high levels of serum IgE in these mice apparently was dependent on the overproduction of IL-4 and IL-5, because treatment with anti-IL-4 and anti-IL-5 monoclonal antibodies significantly inhibited these responses.4 Collectively, these results suggest that the lack of expression or function of NFAT1 could promote the development of allergic disease.



  1. Rao, A. et al. (1997) Annu. Rev. Immunol. 15:707.
  2. Xanthoudakis, S. et al. (1996) Science 272:892.
  3. Hodge, M.R. et al. (1996) Immunity 4:397.
  4. Viola, J.P.B. et al. (1998) Blood 91:2223.