1. The Tumor Necrosis Factor α-dependent Activation of the Human Mediterranean Fever (MEFV) Promoter Is Mediated by a Synergistic Interaction between C/EBPβ and NFκB p65.
- Author
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Papin, Stéphanie, Cazeneuve, Cécile, Duquesnoy, Philippe, Jéru, Isabelle, Sahali, Djillali, and Amselem, Serge
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PROMOTERS (Genetics) , *TUMOR necrosis factors , *GENE expression , *GENETIC transcription , *INFLAMMATION , *NF-kappa B - Abstract
MEFV is a gene expressed specifically in myeloid cells and whose mutations underlie an autosomal recessive auto-inflammatory disease, called familial Mediterranean fever (FMF), characterized by recurrent episodes of serosal inflammation. This gene, which encodes a protein with unclear physiological functions, has been shown to be up-regulated by the pro-inflammatory cytokine tumor necrosis factor α (TNFα). However, the mechanism of this regulation is unknown, and the MEFV promoter is still to be characterized. Here, we show that 243 bp of the 5'-flanking region of the human MEFV gene are sufficient to direct high level expression of MEFV in TNFα-treated cells. The TNFα-induced expression of MEFV is dependent on both NFκB p65 and C/EBPβ that bind to evolutionarily conserved sites located, in the human promoter, at positions -163 and -55, respectively. As shown by a series of transcription and gel shift assays performed with wild-type and mutated promoter sequences, these two transcription factors act differently on the TNFα-dependent transcription of MEFV: C/EBPβ is the key regulatory factor required to confer cell responsiveness to TNFα, whereas NFκB p65 increases this response by means of a synergistic interaction with C/EBPβ that is dependent on the integrity of the identified -55 C/EBP binding site. Given the phenotype of patients with FMF, this C/EBP-NFκB interaction may represent a key step in the control of an inflammatory response that is abnormally high in this disease. These data, which shed novel light on the pathophysiology of FMF, represent an unusual example of cross-talk between C/EBP and NFκB pathways in TNFα signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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