INTERLEUKIN-6 OVERCOMES P21 WAF1 UP-REGULATION AND G1 GROWTH ARREST INDUCED BY DEXAMETHASONE AND INTERFERON-GAMMA IN MULTIPLE-MYELOMA CELLS

Interleukin-6 (IL-6) is a growth factor for multiple myeloma (MM) cell s and can inhibit MM cell apoptosis. Our recent studies show that IL-6 facilitates MM cell growth via phosphorylation of retinoblastoma prot ein (PRE); however, the effects of IL-6 on those cyclins, cyclin-depen dent kinases (CDKs), and CDK inhibitors (CDIs) that are known to regul ate phosphorylation of pRB have not been defined in MM cells. In the p resent report, we cultured MM cell lines and patient cells with IL-6 a nd/or dexamethasone (Dex) and characterized changes in cell cycle; exp ression and association of cyclins, CDKs, and CDIs; and phosphorylatio n of pRB. Dex induced G1 growth arrest in MM cells, whereas IL-6 facil itated G1 to S phase transition; moreover, the effect of Dex was block ed by IL-6. p21WAF1 (p21) protein was constitutively expressed in the majority of MM cells independent of the status of p53. Ifs expression was upregulated by Dex and downregulated by IL-6; again, IL-6 inhibite d the increase in p21 triggered by Dex. These alterations in p21 expre ssion in MM cells were associated with changes in p21 binding to CDK2, CDK4, and CDK6; CDK2, CDK4, and CDK6 kinase activities; and phosphory lation of pRB. In contrast, expression of G1 cell cycle regulatory pro teins, including p27KIP1, cyclin D2, and cyclin E, was not altered in MM cells cultured with Dex and/or IL-6. Finally, interferon-gamma (IFN -gamma) also induced G1 growth arrest and upregulated p21 protein expr ession; as with Dex, affects of IFN-gamma were inhibited by IL-6. Our results therefore show that changes in cell cycle distribution in MM c ells triggered by Dex, IL-6, and IFN-gamma correlate with changes in p 21 protein expression and implicate p21 in the coupling of Dex-, IL-6- , and IFN-gamma-related signals to G1 cell cycle regulation in MM cell s. (C) 1997 by The American Society of Hematology.