INTERLEUKIN-6 INHIBITS FAS-INDUCED APOPTOSIS AND STRESS-ACTIVATED PROTEIN-KINASE ACTIVATION IN MULTIPLE-MYELOMA CELLS

Fas belongs to the family of type-1 membrane proteins that transduce a poptotic signals. In the present studies, we characterized signaling d uring Fas-induced apoptosis in RPMI-8226 and IM-9 multiple myeloma (MM ) derived cell lines as well as patient plasma cell leukemia cells. Tr eatment with anti-pas (7C11) monoclonal antibody (MoAb) induced apopto sis, evidenced by internucleosomal DNA fragmentation and propidium iod ide staining, and was associated with increased expression of c-jun ea rly response gene. We also show that anti-fas MoAb treatment is associ ated with activation of stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK); however, no detectable incre ase in extracellular signal-regulated kinases (ERK1 and ERK2) activity was observed. Because interleukin-6 (IL-6) is a growth factor for MM cells and inhibits apoptosis induced by dexamethasone and serum starva tion, we examined whether IL-6 affects anti-fas MoAb-induced apoptosis and activation of SAPK or p38 MAPK in MM cells. Culture of MM cells w ith IL-6 before treatment with anti-fas MoAb significantly reduced bot h DNA fragmentation and activation of SAPK, without altering induction of p38 MAPK activity. These results therefore suggest that anti-fas M oAb-induced apoptosis in MM cells is associated with activation of SAP K, and that IL-6 may both inhibit apoptosis and modulate SAPK activity . (C) 1997 by The American Society of Hematology.