Modulation of Apoptosis with Cytokines in B-Cell Chronic Lymphocytic Leukaemia

Abstract

In B chronic lymphocytic leukaemia (B-CLL) non-proliferating peripheral blood (PB) B cells have a long life span in vivo. In cultures, these cells die spontaneously by apoptosis. Interleukin (IL) 4 inhibits spontaneous apoptosis (SA) and promotes survival of B-CLL B cells in vitro. No such effect is observed in PB B cells from normal healthy donors. The anti-apoptotic effect of IL4 is independent of mitogen-induced cell activation but depends on the concentration of IL4. The protective effect of IL4 is specific and it is significantly reduced or abolished with anti-IL4 antibody. Interferon (IFN)-gamma (γ) and alpha- (α) IFN also protect B-CLL B cells from apoptosis in vitro. Sera from B-CLL patients have increased levels of IFN-γ when compared with sera from healthy donors. In addition, B-cells in B-CLL express detectable levels of IFN-γ mRNA. Other cytokines, namely IL1, IL2, IL6 and IL7 do not affect SA of B-CLL B cells. By contrast, IL5 and antibody to apolipoprotein-1 (APO-1) receptor increase SA significantly and in a dose-dependent manner. Interleukin 4 protects B-CLL B cells from IL5-, anti(α) APO-1- and steroid-induced apoptosis. The mode of action of the cytokines inducing apoptosis or protecting B-CLL B cells from dying is largely unknown. Recently the bcl-2 proto-oncogene has been associated with prolonged cell survival. However, the involvement of bcl-2 in spontaneous, cytokine-induced or steroid-induced apoptosis in B-CLL has been controversial. Some authors have reported down-regulation of bcl-2 protein expression in B-CLL B-cells undergoing S A or in steroid-treated cells with IL4 preventing this down-regulation. By contrast, others observed no significant loss of bcl-2 protein expression in steroid-, αAPO-1- and IL5-treated cells when compared with untreated or fresh cells. Also, no correlation between bcl-2 protein expression and protection with IL4 has been reported. In conclusion, in B-CLL IL4, IFN-γ and α-IFN promote the survival of the leukaemic cells. These cytokines may therefore be involved in the pathogenesis of the B-CLL.