Rifampicin inhibits CD95-mediated apoptosis of Jurkat T cells via glucocorticoid receptors by modifying the expression of molecules regulating apoptosis.
Rifampicin and its analogues are increasingly used in the treatment and prophylaxis of mycobacterial infections. Recently, it has been demonstrated that rifampicin binds to and activates glucocorticoid receptors (GR). Glucocorticoids may inhibit or promote apoptosis in various cell types. Therefore, we investigated the effect of rifampicin on anti-CD95-induced apoptosis in Jurkat T cells. Rifampicin, in a concentration-dependent manner, inhibited anti-CD95-induced apoptosis. Furthermore, rifampicin down-regulated the expression of Bax and CD95L and up-regulated the expression of Bcl-2, Bcl-xL, and Flice-inhibitory protein-L (FLIPL); however, rifampicin had no effect on CD95 or XIAP expression. Rifampicin did not inhibit the binding of anti-CD95 monoclonal antibody to CD95 receptor. A GR-specific antagonist RU480 reversed the inhibition of apoptosis by rifampicin. Furthermore, rifampicin failed to inhibit anti-CD95-induced apoptosis in a dominant negative IKBalpha (IKBaM) Jurkat T cells. Taken together, these findings suggest that rifampicin inhibits anti-CD95-induced apoptosis in Jurkat T cells by modulating the expression of various molecules regulating apoptosis and its effect appears to be mediated via GR and at least in part through NF-kappaB signaling pathway.
Yerramasetti
Rama
R
Division of Basic and Clinical Immunology University of California, Irvine 92697, USA.
Gollapudi
Sastry
S
Gupta
Sudhir
S
D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000378:metabolism*
D000904:Antibiotics, Antitubercular; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D012293:Rifampin