INDUCTION OF CELL-CYCLE ARREST AND B-CELL TERMINAL DIFFERENTIATION BYCDK INHIBITOR P18(INK4C) AND IL-6

Cell cycle arrest and cell death are tightly coupled to terminal diffe rentiation of B cells to plasma cells in vivo. This process was recapi tulated in vitro by stimulation of IgG-bearing human B lymphoblastoid cells with interleukin-6 (IL-6), which led to orderly cell cycle arres t, differentiation, and apoptosis. In terminally differentiated plasma cytoid cells, phosphorylation of pRb was suppressed, correlating with the activation of the D-type cyclin-dependent kinase (CDK) inhibitors p18(INK4c) and p21(WAF1/CIP1). The expression of CDK6, however, remain ed unchanged. Activation of p18 by IL-6 was rapid, concomitant with ma rked enhancement of its association with CDK6 and cell cycle arrest. O verexpression of p18 in IgM-bearing lymphoblastoid cells, which differ entiated in response to IL-6 but did not exit the cell cycle, reconsti tuted coupled differentiation and cell cycle arrest. Thus, CDK inhibit ors, in particular p18, are likely to play a pivotal role in controlli ng cell cycle arrest and cell death in terminal differentiation of lat e-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6.