Intracellular signaling events associated with the induction of proliferation of normal human B lymphocytes by two different antigenically related human B cell growth factors (high molecular weight B cell growth factor (HMW-BCGF) and the complement factor Bb).
High molecular weight B cell growth factor (HMW-BCGF) and the complement component, Factor B, are antigenically related. HMW-BCGF and the physiologic Factor B activation fragment Bb, are both mitogenic for B lymphocytes and compete for binding to the B cell plasma membrane (Peters, M., Ambrus, J. L., Jr., Fauci, A., and Brown, E. (1988) J. Exp. Med. 168, 1225-1235). To understand which second messengers that occur after ligand-receptor interaction are associated with mitogenesis, we have examined the early signaling events after stimulation of activated B cells with these related growth factors. HMW-BCGF but not Bb increased [cAMP]i with a maximum between 45 and 60 min after stimulation. The increase in [cAMP]i was inhibited by indomethacin, suggesting that prostaglandin synthesis is involved in this response. Increase in [cAMP]i induced by HMW-BCGF, cholera toxin, or dibutyryl cAMP was associated with increased expression of the HMW-BCGF receptor, but there was no increase in proliferation of activated B cells when they were stimulated with cAMP agonists other than HMW-BCGF. These data suggest that cAMP is associated with regulation of receptor expression but is neither necessary nor sufficient for induction of proliferation. Both HMW-BCGF and Bb increased cellular levels of diacylglycerol and a water-soluble molecule which could be labeled with both [3H]myoinositol and [14C] glucosamine. However, only HMW-BCGF induced increases in intracellular calcium. Thus, two antigenically related B cell growth factors, HMW-BCGF and Bb, produce overlapping but distinct sets of second messengers after incubation with Sac-activated B cells. Since both induced increases in diacylglycerol and water-soluble inositol, one or both of these molecules may be involved in the proliferative signal generated by the related growth factors. In contrast, the increase in [cAMP]i caused by HMW-BCGF but not Bb is involved in the signal to increase HMW-BCGF receptor expression, but is unrelated to proliferation.
Ambrus
J L
JL
Department of Medicine, Jewish Hospital of St. Louis, Washington University Medical Center, Missouri 63110.
Chesky
L
L
Chused
T
T
Young
K R
KR
McFarland
P
P
August
A
A
Brown
E J
EJ
D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division; D002772:Cholera Toxin / Q000494:pharmacology; D011415:Complement Factor B / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D004075:Diglycerides / Q000096:biosynthesis; D005227:Fatty Acids / Q000378:metabolism; D005944:Glucosamine / Q000378:metabolism; D006801:Humans; D007294:Inositol / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D008970:Molecular Weight; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects*
D004075:Diglycerides; D005227:Fatty Acids; D015847:Interleukin-4; D007294:Inositol; D003994:Bucladesine; D002772:Cholera Toxin; D000242:Cyclic AMP; D011415:Complement Factor B; D005944:Glucosamine