Differential modulation of interleukin-2-and interleukin-4-mediated early activation of normal human B lymphocytes by the caspase inhibitor zVAD-fmk.
Caspases are a group of cysteine-related proteases that control the process of apoptosis and may also be involved in the control of lymphocyte activation. We show here that the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp (Ome)-fluoromethylketone (zVAD-fmk) prevents the proliferation of resting human B tonsilar lymphocytes mediated by the B cell mitogen SAC or the combination of anti-mu Ab and IL-2. zVAD-fmk inhibits IL-2-induced phosphorylation of the retinoblastoma protein, and cyclin D2 expression. However, neither the IL-2-mediated proliferation of cycling activated B cells nor that of lymphoma cells were inhibited by zVAD-fmk, suggesting that only the early steps of SAC- or IL-2-mediated B cell activation were sensitive to the inhibitory properties of zVAD-fmk. Our data also demonstrated that the inhibitory effect of zVAD-fmk was not observed when B cells were activated with IL-4 in the presence of either anti-mu Ab or anti-CD40 Ab. Thus, our results suggest that caspase activation is required for the IL-2-mediated entry of primary B lymphocytes into the cell cycle and show that caspase activation plays different roles in IL-2- and IL-4-mediated B cell proliferation.
Mouhamad
Shahul
S
INSERM U.542, Hôpital Paul Brousse, Bâtiment Lavoisier, 14 Avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France.
Arnoult
Damien
D
Auffredou
Marie-Thérèse
MT
Estaquier
Jérome
J
Vazquez
Aimé
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007376:Interleukin-2; D008934:Mitogens; D011994:Recombinant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D015847:Interleukin-4