TY - JOUR
T1 - NFAT but not NF-{kappa}B is critical for transcriptional induction of the prosurvival gene A1 after IgE receptor activation in mast cells
AU - Ullerås, Erik
AU - Karlberg, Mats
AU - Westerberg, Christine Möller
AU - Alfredsson, Jessica
AU - Gerondakis, Steve
AU - Strasser, Andreas
AU - Nilsson, Gunnar
PY - 2008/3/15
Y1 - 2008/3/15
N2 - FceRI-activation-induced survival of mast cells is dependent on the expression and function of the prosurvival protein A1. The expression of A1 in lymphocytes and monocytes has previously been described to be transcriptionally regulated by NF-k-B. Here we demonstrate that the expression of A1 in mast cells is not dependent on NF-kB but that NFAT plays a crucial role. FceRI-induced A1 expression was not affected in mast cells overexpressing an IkB-u super-repressor or cells lacking NF-kB subunits RelA, c-Rel, or c-Rel plus NF-K-B1 p50. In contrast, inhibition of calcineurin and NFAT by cyclosporin A abrogated the expression of A1 in mast cells on FctRI-activation but had no effect on lipopolysaccharide-induced expression of A1 in J774A.1 monocytic cells. Cyclosporin A also inhibited luciferase expression in an A1 promoter reporter assay. A putative NFAT binding site in the A1 promoter showed inducible protein binding after FceRI crosslinking or treatment with ionomycin as detected in a band shift assay or chromatin immunoprecipitation. The binding protein was identified as NFAT1. Finally, mast cells expressing constitutively active NFAT1 exhibit increased expression of A1 after FceRI-stimulation. These results indicate that, in FceRI stimulated mast cells, A1 is transcriptionally regulated by NFAT1 but not by NF-kB.
AB - FceRI-activation-induced survival of mast cells is dependent on the expression and function of the prosurvival protein A1. The expression of A1 in lymphocytes and monocytes has previously been described to be transcriptionally regulated by NF-k-B. Here we demonstrate that the expression of A1 in mast cells is not dependent on NF-kB but that NFAT plays a crucial role. FceRI-induced A1 expression was not affected in mast cells overexpressing an IkB-u super-repressor or cells lacking NF-kB subunits RelA, c-Rel, or c-Rel plus NF-K-B1 p50. In contrast, inhibition of calcineurin and NFAT by cyclosporin A abrogated the expression of A1 in mast cells on FctRI-activation but had no effect on lipopolysaccharide-induced expression of A1 in J774A.1 monocytic cells. Cyclosporin A also inhibited luciferase expression in an A1 promoter reporter assay. A putative NFAT binding site in the A1 promoter showed inducible protein binding after FceRI crosslinking or treatment with ionomycin as detected in a band shift assay or chromatin immunoprecipitation. The binding protein was identified as NFAT1. Finally, mast cells expressing constitutively active NFAT1 exhibit increased expression of A1 after FceRI-stimulation. These results indicate that, in FceRI stimulated mast cells, A1 is transcriptionally regulated by NFAT1 but not by NF-kB.
UR - http://www.scopus.com/inward/record.url?scp=42449121864&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-10-053371
DO - 10.1182/blood-2006-10-053371
M3 - Article
C2 - 18182578
AN - SCOPUS:42449121864
SN - 0006-4971
VL - 111
SP - 3081
EP - 3089
JO - Blood
JF - Blood
IS - 6
ER -