NFAT but not NF-κB is critical for transcriptional induction of the prosurvival gene A1 after IgE receptor activation in mast cells

Abstract

IntroductionMast cells are potent effector cells displaying versatile functions during immune responses and as regulators of inflammation. [1][2][3] Many of these functions are executed via activation of the high affinity IgE receptor (Fc⑀RI) and subsequent release of regulatory factors stored in granules. 4 In addition, receptor stimulation initiates signaling cascades, which result in activation of specific genes encoding cytokines and growth factors. 5 In some cases, the activated transcription has been shown to be mediated by members of the NF-B and/or NFAT transcription factor families. 6 These transcription factors are sequestered in an inactive state in the cytosol of resting cells, and after cell stimulation they are translocated to the nucleus where they bind target DNA sequences and activate transcription.In contrast to granulocytes and certain other hematopoietic cells, mature mast cells are not recruited from the bloodstream in response to inflammatory signals. Instead, long-lived mast cells are located in the tissues, and their relative abundance and increase during inflammation are regulated at the level of cell migration within the tissue and the control of survival/apoptosis. 7,8 We and others have previously demonstrated that, after stimulation of the high affinity IgE receptor, Fc⑀RI, mast cell survival is substantially enhanced. [9][10][11] These cells can therefore undergo a new round of activation and thus contribute again to an inflammatory response. [12][13][14] The activation-induced survival effect is attributed to the specific up-regulation of the antiapoptotic Bcl-2 family member A1/Bfl-1 gene. 10,15 Accordingly, mast cells from A1-deficient mice do not exhibit activation-induced survival after Fc⑀RI crosslinking. 10 A1 is expressed and exerts its antiapoptotic function not only in mast cells but also in endothelial cells, T and B lymphocytes, neutrophils, and macrophages. [16][17][18][19][20][21] In these cell types, expression of the A1 gene is induced by diverse stimuli, such as inflammatory cytokines, lipopolysaccharide (LPS), CD40-activation, and antigen receptor (TCR or sIg) receptor activation. The increased transcription of the A1 gene in lymphocytes has been demonstrated to be dependent on the NF-B transcription factor pathway. [22][23][24][25] It was shown that antigen receptor crosslinking-mediated A1 induction is abolished in NF-B-deficient cells and that enforced NF-B overexpression increases A1 levels. Moreover, a functional NF-B binding site has been mapped within the A1 promoter.Knowledge of the mechanisms leading to A1 induction after Fc⑀RI activation could identify possible ways to interfere with this pathway and thereby control mast cell survival and its downstream effects. In this report, we examine these signaling pathways in mast cells and show that, in contrast to other cell types and stimuli, NF-B is not responsible for the IgE receptor activation-mediated induction of A1. Instead, this study indicates that in mast cells, a member of the NFAT class of transcript...

NFATc1 Induction in Peripheral T and B Lymphocytes

“…The predominant NFATc1/aA induction correlated well with an increased binding of NFATc1 to the P1 promoter. This is shown in ChIP assays in which the binding of NFATc1 and c2 to the P1 promoter was compared with the binding to the Il4 and Tnf promoters, two well-known NFAT targets (23,24), and the Bcl2a1a/A1 and Nr4a1/nur77 promoters, two putative NFAT targets (25,26) (Fig. 7B).…”

NFAT control of innate immunity

“…76,77 Recently, the mechanism of this prolonged survival has been linked to the NFAT-dependent transcription of the antiapoptotic Bcl2 family member gene A1/Bfl-1. 78 The antiapoptotic function of A1 has also been described in neutrophils and macrophages. [79][80][81] IgE crosslinking on mast cells leads to Ca 2ϩ flux followed by NFAT translocation and up-regulation of A1 expression, which may explain previous data indicating that increased Ca 2ϩ levels are beneficial to mast cell survival.…”

Mast Cells as Targets of Pimecrolimus

“…Ullerås et al [32] reported that Fc RI-mediated activation induced A1 gene expression, and it was regulated by the calcineurin/NFAT pathway. CsA was found to reduce Fc RI-mediated mast cells survival through inhibition of calcineurin/NFAT pathway and subsequent reduced A1 protein expression.…”