Effect of IL-4 and IL-6 on the proliferation and differentiation of B-chronic lymphocytic leukemia cells.

The proliferation and differentiation of purified malignant B cells from nine patients with chronic lymphocytic leukemia (B-CLL) were studied in vitro. We have demonstrated before that tumour necrosis factor alpha (TNF-alpha), in combination with low dose phorbol myristic acid (PMA) (0.1 ng/ml), can induce proliferation in these purified B-cell populations and that this TNF-alpha-induced proliferation is completely inhibited by the addition of interleukin 4 (IL-4). In this study we demonstrate that IL-6 is also able to inhibit this TNF-alpha-induced proliferation. Inhibition is maximal with 400 pg/ml of IL-6. With the use of neutralizing antibodies we show that the inhibition by IL-4 and IL-6 are independent processes. In contrast, investigation of differentiation as measured by immunoglobulin M (IgM) production, showed that in combination with PMA (1 ng/ml), IL-4 is the main cytokine to induce differentiation of these B-CLL cells. That we were indeed measuring differentiation of the malignant B cells could be demonstrated by the specific production of IgM/kappa or IgM/lambda. No induction of IgG or IgE production could be detected. In contrast to IL-4, in the majority of cases IL-6 does not play a role in the induction of differentiation of B-CLL cells. However, in two out of nine B-CLL patients we found that at low PMA concentrations (0.1 ng/ml), TNF-alpha can induce both proliferation and differentiation. In agreement with what was found for the proliferative response, this TNF-alpha-induced IgM production is inhibited both by IL-4 and IL-6. The possible therapeutic implications of our findings are briefly discussed.