Abstract
The engagement of antigen receptor can initiate apoptosis of T lymphocytes through the induced expression of Fas ligand (FasL). Forskolin, an activator of the cAMP/PKA pathway, results in antagonism of Fas-dependent, activation-induced cell death (AICD) by suppressed expression of the FasL. We report that forskolin-mediated induction of inducible cAMP early repressor (ICER) correlates with transcriptional attenuation of FasL expression in the AICD model 2B4 T cell hybridoma. ICER is inducible in human peripheral blood CD3(+) T cells, but in CD19(+) B cells, its induction is less responsive to forskolin treatment. Increased expression of ICER correlates with decreased FasL expression in both T and NK cells. ICER binds specifically to the proximal DNA binding site of the nuclear factor of activated T cells (NFAT) in the FasL promoter and in the presence of the minimal NFAT DNA-binding domain, the proximal NFAT motif allows ICER and NFAT to form an NFAT/ICER ternary complex in vitro. Moreover, in the activated 2B4 T cell hybridoma, the proximal NFAT motif participates in the down-regulation of the FasL promoter mediated by ICER. These findings provide further insight into the mechanism involved in cAMP-mediated transcriptional attenuation of FasL expression in T and NK lymphocytes.
MeSH terms
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Antigens, CD19
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Binding Sites
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Biomarkers
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CD13 Antigens
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Cell Line
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Cells, Cultured
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Colforsin / pharmacology
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Cyclic AMP Response Element Modulator
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Fas Ligand Protein
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Gene Expression Regulation*
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Humans
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Jurkat Cells
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Killer Cells, Natural / cytology
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / metabolism*
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Membrane Glycoproteins / genetics*
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NFATC Transcription Factors
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Nuclear Proteins*
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Promoter Regions, Genetic*
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RNA, Messenger / biosynthesis
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Repressor Proteins / physiology*
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism*
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
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Transcriptional Activation
Substances
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Antigens, CD19
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Biomarkers
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DNA-Binding Proteins
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FASLG protein, human
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Fas Ligand Protein
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Membrane Glycoproteins
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NFATC Transcription Factors
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Nuclear Proteins
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RNA, Messenger
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Repressor Proteins
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Transcription Factors
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Cyclic AMP Response Element Modulator
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Colforsin
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CD13 Antigens