Nuclear Factor of Activated T Cells (Nfat) Is a Possible Target for Dexamethasone in Thymocyte Apoptosis

Abstract

Cell death plays a critical role in the generation of an effective immune system. During maturation T lymphocytes are generated, censored and eliminated in the thymus. These events are temporally associated with developmental changes in the levels of transcription factors including NFAT. The NFAT transcription factor (nuclear factor of activated T cells) is implicated in the regulation of T-lymphocyte proliferation and transcriptional activation of genes encoding lymphokines. It has been demonstrated that discontinuities in the inducibility of NFAT and AP-1 transcription factors occur during transition of immature thymocytes into cortical thymocytes which are eliminated by apoptosis. To understand the molecular basis of these developmental intrathymic changes, we studied DNA-binding activities of transcription factors during dexamethasone-induced apoptosis of immature thymocytes. We observed a specific loss of NFAT DNA-binding activity after dexamethasone treatment. It correlated with a selective disappearance of one out of two AP-1 complexes. Our data suggest that NFAT complex is a possible target in dexamethasone-induced apoptosis.

Increased expression of NFATc1 in giant cell lesions of the jaws, cherubism and brown tumor of hyperparathyroidism

“…This protein forms a complex with the protein AP-1 to bind in specific DNA sites. Loss of NFAT:AP-1 complex activity in the nucleus promotes apoptosis of these cells (16). Glucocorticoids impair this complex formation and induce apoptosis of the immature thymocytes (17).…”

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

“…5 The repression of AP-1 transcription factor activity in corticosteroid-treated lymphocytes is accompanied by repression of other prosurvival transcription factors, including the nuclear factor of activated T lymphocytes (NFAT). 6 NFAT is composed of two components, NFATp and AP-1; the dexamethasone-induced decrease in NFAT activity is due to a decrease in AP-1 activity. 6 Also, Thompson and coworkers 7 have provided substantial evidence that downregulation of c-Myc accompanies the induction of apoptosis by corticosteroids, and that c-Myc overexpression inhibits corticosteroid-induced apoptosis.…”

“…6 NFAT is composed of two components, NFATp and AP-1; the dexamethasone-induced decrease in NFAT activity is due to a decrease in AP-1 activity. 6 Also, Thompson and coworkers 7 have provided substantial evidence that downregulation of c-Myc accompanies the induction of apoptosis by corticosteroids, and that c-Myc overexpression inhibits corticosteroid-induced apoptosis.…”

Cell specific effects of glucocorticoid treatment on the NF-kappa Bp65/Ikappa Balpha system in patients with Crohn's disease

“…The molecular mechanisms underlying the therapeutic effects of glucocorticoids on chronic inflammation are poorly understood. However, there is growing evidence that they exert part of their action by downregulating gene expression by interfering with the activity of transcription factors such as STAT-1,25 NFAT-1,26 AP-1,27 and NF-κB 26 28 The highly immunosuppressive and anti-inflammatory action of glucocorticoids is at least in part related to a glucocorticoid dependent repression of NF-κB mediated gene expression 2…”