MODULATION OF THE P27(KIP1) CYCLIN-DEPENDENT KINASE INHIBITOR EXPRESSION DURING IL-4-MEDIATED HUMAN B-CELL ACTIVATION

IL-4 activates resting B cells and, in conjunction with cosignals such as anti-IgM (anti-mu) Ab or CD40 ligand, modulates progression of B c ells through the cell cycle, leading to proliferation. In this study, we show that the mitogenic combination of IL-4 and anti-mu Ab triggere d induction of cyclin D3 and up-regulated cyclin-dependent kinase (cdk ) 6 expression, whereas such regulation was not observed in B cells ac tivated by IL-4 or anti-mu Ab alone. Furthermore, cyclin D3 immunoprec ipitated fron as associated with cdk6, and the cyclin D3/cdk6 complex was able to phosphorylate recombinant retinoblastoma protein in vitro. In addition, B cells activated with either IL-4 or 1L-13 alone expres sed a higher amount of p27(kip1) (p27) cdk inhibitor than nonstimulate d cells. In contrast, p27 expression was decreased when cells were act ivated with mitogenic combinations of IL-4 and anti-mu Ab or anti-CD40 mAb. We also observed that the IL-4-mediated inhibition of the prolif eration of anti-mu/IL-2- or anti-mu/phorbol 12,13-dibutyrate-activated human leukemic B cells was associated with the maintenance of large a mounts of p27 in these cells. These data suggest that IL-4 controls B cell proliferation by action during at least two steps of the regulati on of the cell cycle, cyclin D3/cdk6 complex regulation and p27 inhibi tor expression.