REGULATION OF ALLERGIC INFLAMMATION AND EOSINOPHIL RECRUITMENT IN MICE LACKING THE TRANSCRIPTION FACTOR NFAT1 - ROLE OF INTERLEUKIN-4 (IL-4) AND IL-5

Transcription factors of the NFAT (nuclear factor of activated T cells ) family regulate the expression of many genes encoding immunoregulato ry cytokines and cell surface proteins during the immune response. The NFAT protein NFAT1 (NFATp) is expressed and functional in T cells, B cells, mast cells, and natural killer cells. Here we report a detailed analysis of the enhanced eosinophil responses of NFAT1-deficient mice , observed in an in vivo model of allergic inflammation. In addition t o the pleural eosinophilia described previously, NFAT1(-/-) mice that have been sensitized with antigen display a significant increase, rela tive to wildtype mice. in the numbers of eosinophils in bone marrow en d peripheral blood, After restimulation with antigen in vitro, antigen -responsive T cells from the draining lymph nodes of NFAT1(-/-) mice s how increased expression of mRNA encoding the Th2 cytokines interleuki n-4 (IL-4), IL-5, and IL-13. Consistent with this finding, there is a pronounced increase in the levels of IL-5 and IL-13 in the pleural cav ities of sensitized NFAT1(-/-)mice after allergen challenge in vivo. F urthermore, development of eosinophilia depends on overexpression of I L-4 and IL-5. because it is strongly inhibited by administration of ne utralizing antibodies to either of these cytokines. These results indi cate that NFAT1-deficient mice are prone to develop a classically alle rgic phenotype characterized by eosinophilia and increased production of Th2 cytokines. Thus, the presence of NFAT1 might inhibit the allerg ic response, perhaps by interfering with the development of Th2 immune responses, and the lack or dysfunction of NFAT1 could potentially und erlie certain cases of atopic disease. (C) 1998 by The American Societ y of Hematology.