Differential inhibition of interleukin 2- and interleukin 4-mediated human B cell proliferation by ionomycin: a possible regulatory role for apoptosis.
Surface immunoglobulin (Ig) cross-linking by anti-IgM (mu) antibodies leads to B cell activation resulting in numerous early biochemical events including an increase in intracellular [Ca2+]. Furthermore, anti-mu-activated B cells become able to proliferate in response to interleukin (IL)2 and IL4. These studies examined the effect of the calcium ionophore ionomycin, an enhancer of cytoplasmic [Ca2+] levels, on IL2 and IL4-mediated proliferation of anti-mu-stimulated normal human B cells. Ionomycin inhibited the proliferative response of anti-mu-activated B cells to IL4. In contrast, IL2 and phorbol 12,13 dibutyrate (PBu2)-mediated B cell proliferation was refractory to the growth inhibitory effects of ionomycin. In an attempt to delineate a possible mechanism(s) for this differential growth effect of ionomycin, we first studied direct effects of ionomycin on activated B cells. Our data suggested that ionomycin induced DNA fragmentation in anti-mu-costimulated B cells. Interestingly, in contrast to PBu2, IL4 did not prevent ionomycin-dependent DNA fragmentation. Importantly, H7, an inhibitor of protein kinase C activation, down-regulated only the IL2 and PBu2-driven B cell proliferation but not B cell proliferative response to IL4. These results suggest that putative protein kinase C activation, either by direct treatment with phorbol ester or during IL2 signaling, counteracts the inhibitory effects of ionomycin. In contrast, IL4 signaling does not exhibit the same protective properties.
INSERM U 131, Clamart, France.
A
A
Vazquez
M T
MT
Auffredou
N
N
Chaouchi
J
J
Taieb
S
S
Sharma
P
P
Galanaud
G
G
Leca
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects*; D004249:DNA Damage; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors
D007376:Interleukin-2; D015850:Interleukin-6; D007546:Isoquinolines; D010879:Piperazines; D015847:Interleukin-4; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D002118:Calcium