Bestatin, an inhibitor of aminopeptidase B, suppresses the proliferation and differentiation of human B-cells in vitro

Bestatin, an inhibitor of aminopeptidase B, was examined for its effect on B-cell activation. Small, dense B-cells from human tonsil samples were isolated by Percoll density gradients from non-rosetted (E-) cells and were used as target cells. Although bestatin was not cytotoxic towards B-cells, it inhibited the proliferative response of B-cells induced by SAC- or PMA-stimulation. The inhibition of cell proliferation by bestatin was manifested as cell arrest caused by the selective block of G1b to S phase transition. This inhibitory effect was prevented by the addition of B-cell growth factor (BCGF) or interleukin-2 (IL-2). The presence of BCGF or IL-2 at the initiation of the culture prevented the bestatin-mediated suppressive effect on B-cell proliferation. Bestatin also has a direct inhibitory effect on the differentiation of B-cells independent of its suppressive effect on B-cell proliferation, which was not relieved by T-cell help. Conversely, bestatin suppressed neither proliferation nor Ig secretion of human B lymphoblastoid cell lines, although aminopeptidase activities on the membrane of these cell lines were strongly inhibited by bestatin. These results indicated that bestatin selectively suppressed normal B-cell proliferation and differentiation. Although several studies have demonstrated that bestatin has immunopotentiating effects in tumor-bearing subjects, the above results indicated that the mechanism of immunopotentiation by bestatin is not a direct stimulatory effect on B-cells.