NF-kappaB functions as both a proapoptotic and antiapoptotic regulatory factor within a single cell type.
Recently NF-kappaB has been shown to have both proapoptotic and antiapoptotic functions. In T cell hybridomas, both T cell activators and glucocorticoids induce apoptosis. Here we show that blockade of NF-kappaB activity, using a dominant negative IkappaBalpha, has opposite effects on these two apoptotic signals. Treatment with PMA plus ionomycin (P/I) results in the upregulation of Fas Ligand (FasL) and induction of apoptosis. Inhibition of NF-kappaB activity inhibits the P/I mediated induction of FasL mRNA and decreases the level of apoptosis in these cultures, thus establishing NF-kappaB as a proapoptotic factor in this context. Conversely, inhibition of NF-kappaB confers a tenfold increase in glucocorticoid mediated apoptosis, establishing that NF-kappaB also functions as an antiapoptotic factor. We conclude that NF-kappaB is a context-dependent apoptosis regulator. Our data suggests that NF-kappaB may function as an antiapoptotic factor in thymocytes while functioning as a proapoptotic factor in mature peripheral T cells.
Lin
B
B
Program in Toxicology, Denver, Colorado 80262, USA.
Williams-Skipp
C
C
Tao
Y
Y
Schleicher
M S
MS
Cano
L L
LL
Duke
R C
RC
Scheinman
R I
RI
D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D053222:Fas Ligand Protein; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006825:Hybridomas; D020672:I-kappa B Proteins; D015759:Ionomycin / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics; D008934:Mitogens / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010835:Phytohemagglutinins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D008934:Mitogens; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010835:Phytohemagglutinins; D000072000:NF-KappaB Inhibitor alpha; D015759:Ionomycin; D003907:Dexamethasone