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Tumor necrosis factor‐α‐induced caspase‐1 gene expression
Author(s) -
Jain Nishant,
Sudhakar Ch,
Swarup Ghanshyam
Publication year - 2007
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2007.05969.x
Subject(s) - tumor necrosis factor alpha , microbiology and biotechnology , biology , small hairpin rna , gene expression , caspase 1 , gene , apoptosis , gene knockdown , immunology , programmed cell death , biochemistry
Tumour necrosis factor‐α (TNF‐α) is a cytokine that is involved in many functions, including the inflammatory response, immunity and apoptosis. Some of the responses of TNF‐α are mediated by caspase‐1, which is involved in the production of the pro‐inflammatory cytokines interleukin‐1β, interleukin‐18 and interleukin‐33. The molecular mechanisms involved in TNF‐α‐induced caspase‐1 gene expression remain poorly defined, despite the fact that signaling by TNF‐α has been well studied. The present study was undertaken to investigate the mechanisms involved in the induction of caspase‐1 gene expression by TNF‐α. Treatment of A549 cells with TNF‐α resulted in an increase in caspase‐1 mRNA and protein expression, which was preceded by an increase in interferon regulatory factor‐1 and p73 protein levels. Caspase‐1 promoter reporter was activated by the treatment of cells with TNF‐α. Mutation of the interferon regulatory factor‐1 binding site resulted in the almost complete loss of basal as well as of TNF‐α‐induced caspase‐1 promoter activity. Mutation of the p53/p73 responsive site resulted in reduced TNF‐α‐induced promoter activity. Blocking of p73 function by a dominant negative mutant or by a p73‐directed small hairpin RNA reduced basal as well as TNF‐α‐induced caspase‐1 promoter activity. TNF‐α‐induced caspase‐1 mRNA and protein levels were reduced when p73 mRNA was down‐regulated by small hairpin RNA. Caspase‐5 gene expression was induced by TNF‐α, which was inhibited by the small hairpin RNA‐mediated down‐regulation of p73. Our results show that TNF‐α induces p73 gene expression, which, together with interferon regulatory factor‐1, plays an important role in mediating caspase‐1 promoter activation by TNF‐α.