Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression.

Abstract

SummaryB chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of slow-dividing and long-lived monoclonal B cells arrested at the intermediate stage of their differentiation . We previously showed that interleukin 4 (IL4) not only inhibits but also prevents the proliferation of B-CLL cells. We report here that IL-4 protects the B-CLL cells from death by apoptosis (programmed cell death [PCD]) . IL-4 inhibits spontaneous and hydrocortisone (HC)-induced PCD of highly purified B cells from 12 unselected CLL patients, as shown by sustained cell viability and lack of DNA fragmentation . IL1, -2, -3, -5, -6, -7, tumor necrosis factor a, and transforming growth factor (3 have no protective effect . The in vitro rescue from apoptosis by IL-4 is reflected by an increased expression of Bcl-2 protein, a proto-oncogene directly involved in the prolongation of cell survival in vivo and in vitro. Hence, IL-4-treated B-CLL cells express significantly more Bcl-2 than unstimulated, HC-treated, or fresh B-CLL cells. Furthermore, subcutaneous injection of IL4 into one CLL patient enhances Bcl-2 protein expression in the leukemic B cells . These data may suggest that IL-4 prevents apoptosis of B-CLL cells using a Bcl-2-dependent pathway. Given our recent observations that fresh T cells from B-CLL patients express IL-4 mRNA, we propose that IL-4 has an essential role in the pathogenesis of CLL disease, by preventing both the death and the proliferation of the malignant B cells .

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

“…In keeping with previous studies, we found that the addition of recombinant IL-4 prevented the anti-IgM-induced growth arrest and apoptosis ( Figure 1). It has been shown that IL-4 can slow the proliferation of several tumor cell lines, a point confirmed in Figure 1A for CH31 cells [8,9,29]. Importantly, we observed that IL-4 reversed the potent growth inhibition caused by anti-IgM treatment ( Figure 1).…”

“…These effects are not limited to normal cells. In fact, IL-4 can regulate the survival of B-cell chronic lymphocytic leukemia (B-CLL, [8,9]). In this context, it is not surprising that a unique molecular signature of B-cell small lymphocytic lymphoma (SLL) is the elevated expression of the IL-4 receptor alpha chain [10].…”

Analysis of the Major Patterns of B Cell Gene Expression Changes in Response to Short-Term Stimulation with 33 Single Ligands

“…3). Our results also suggest that the ability of IL-4 to promote proliferation as a cofactor is not solely attributed to the up-regulation of antiapoptotic genes, such as Bcl-2, by IL-4 stimulation (35), but it may be due to the synergistic induction of many genes involved in cell proliferation (Fig. 4).…”

Paradoxical Roles of IL-4 in Tumor Immunity

“…According to the immunosurveillance theory, tumor initiation and progression are accompanied by the attack from host immune system (54) With these observations in normal B/T cells, it is easy to imagine that IL-4 promotes the survival of B/T cell-derived tumors. As early as in 1992, Danceca reported that IL-4 inhibited spontaneous and hydrocortisone-induced cell death of malignant B cells purified from patients with B chronic lymphocytic leukemia (67).…”