CYCLOSPORINE-A AND FK506 BLOCK THE NEGATIVE SIGNALING MEDIATED BY SURFACE IGM CROSS-LINKING IN NORMAL HUMAN MATURE B-CELLS

Cross-linking of surface IgM (sIgM) or sIgD by anti-IgM Ab or anti-IgD Ab, respectively, induced DNA synthesis in peripheral blood B cells ( PBL-B). Cell division, determined by the increase in the number of M p hase cells, was also induced when PBL-B were stimulated with anti-IgD Ab plus IL-4 or Staphylococcus aureus Cowan I (SAC), but far less by s timulation with anti-IgM Ab plus IL-4. Anti-IgM Ab did not suppress th e DNA synthesis induced by SAC or anti-IgD Ab plus IL-4, but it did su ppress the cell division induced by them. Thus, sIgM cross-linking gen erates both positive and negative signaling to B-cell proliferation. C yclosporin A (CSA) and FK506 suppressed DNA synthesis and cell divisio n at relatively high concentrations. On the other hand, CSA and FK506 at lower concentrations blocked the anti-IgM Ab-generated inhibition o f cell division without affecting DNA synthesis. Low concentrations of CSA did not affect the cell division induced by anti-IgD Ab plus IL-4 but did increase the cell division induced by SAC or anti-IgM Ab plus IL-4, suggesting that stimulation with SAC, as well as with anti-IgM Ab plus IL-4, generates both positive and negative signals to cell div ision, whereas sIgD lacks the ability to transduce negative signaling.