NUCLEAR FACTOR OF ACTIVATED T-CELLS IS ASSOCIATED WITH A MAST-CELL INTERLEUKIN-4 TRANSCRIPTION COMPLEX

Interleukin 4 (IL-4), an immunoregulatory cytokine, is produced only b y a subset of activated T cells and cells of the mast cell-basophil li neage. The production of IL-4 by mast cells likely represents a signif icant source of this protein in local immune-inflammatory responses in the skin, brain, gastrointestinal, and respiratory tracts, in which m ast cells are prevalent. In the present study, the cis- and trans-acti ng elements that control inducible mast cell IL-4 gene transcription w ere examined and compared with those that function in T cells. We demo nstrate that, as in T cells, sequences between bp -87 and -70 are crit ical for protein association and activation-dependent gene transcripti on and that this region (termed the activation-responsive element regi on) is the target of an inducible, cyclosporin A-sensitive, DNA-protei n interaction. When assessed by electrophoretic mobility shift assays and UV cross-linking analyses, multiple proteins in both T- and mast c ell nuclear extracts associate with the activation-responsive element in vitro, and some of these appear identical. However, distinct protei ns are associated with each of the complexes as well. AP-1 family memb ers are unique to the T-cell-stimulation-dependent complex, whereas ma st cell complexes contain factors that are reactive with anti-nuclear factor of activated T cells p (NF-ATp) and anti-NF-ATc antibodies but have distinct molecular masses compared with those of T-cell-derived N F-AT. Furthermore, an anti-NF-ATp-reactive factor with a molecular mas s of similar to 41 kDa is present in the nuclei of unstimulated cells and binds independently of cell activation, unlike the previously desc ribed NF-AT family members. These data support the idea that there are uniquely regulated, cell lineage-specific transcription factors relat ed to T-cell-derived NF-AT that mediate inducible IL-4 transcription i n mast cells. These differences likely reflect the distinct cell surfa ce signalling requirements for IL-4 production in T and mast cells.