Nuclear factor of activated T cells transcription factor NFATp controls superantigen-induced lethal shock.
Tumor necrosis factor alpha (TNF-alpha) is the key mediator of superantigen-induced T cell lethal shock. Here, we show that nuclear factor of activated T cells transcription factor, NFATp, controls susceptibility to superantigen-induced lethal shock in mice through its activation of TNF-alpha gene transcription. In NFATp-deficient mice, T cell stimulation leads to delayed induction and attenuation of TNF-alpha mRNA levels, decreased TNF-alpha serum levels, and resistance to superantigen-induced lethal shock. By contrast, after lipopolysaccharide (LPS) challenge, serum levels of TNF-alpha and susceptibility to shock are unaffected. These results demonstrate that NFATp is an essential activator of immediate early TNF-alpha gene expression in T cells and they present in vivo evidence of the inducer- and cell type-specific regulation of TNF-alpha gene expression. Furthermore, they suggest NFATp as a potential selective target in the treatment of superantigen-induced lethal shock.
Tsytsykova
A V
AV
Center for Blood Research and Harvard Medical School and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Goldfeld
A E
AE
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D004768:Enterotoxins; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018089:Superantigens; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C031818:enterotoxin B, staphylococcal