IL-4 is a T-cell-derived lymphokine capable of promoting the proliferation and differentiation of normal B-cells following activation by other mechanisms, such as anti-IgM and anti-CD40 antibodies (25-27).
The ability of IL-4 to induce proliferation of CLL leukemic B-cells has been controversial. In fact, IL-4 has been reported to both inhibit and induce a proliferative effect on neoplastic cells from CLL patients in vitro (18,28,29). These contrasting data can possibly be explained by the influence of the different signaling pathways used by various authors for the in vitro activation studies.
It has, instead, been convincingly shown that IL-4 is capable of protecting CLL cells from apoptotic death, both spontaneous and induced by steroids, IL-5, and Fas signaling (30-32). The inhibition of apoptosis mediated by IL-4 was found to correlate with increased levels of bcl-2 (30,32), an association not confirmed by all authors (31). The stage of the disease has no effect on the level of apoptosis inhibition by IL-4, but doses of IL-4 capable of protecting cells from previously treated CLL patients from spontaneous apoptosis were reported to have very little effect on cells from untreated patients. It was thus suggested that increased sensitivity to the anti-apoptotic effect of IL-4 might be one of the mechanisms of acquired drug resistance in CLL (33). This anti-apoptotic effect might have a particular relevance in vivo since non-neoplastic CLL T-cells have been reported to produce increased levels of IL-4, potentially supporting the expansion and accumulation of the neoplastic clone (34-37). Moreover, an autocrine pathway can also be hypothesized: CLL B-cells have in fact been recently found capable of secreting detectable amounts of IL-4 (37).
Despite these preclinical studies, in a recently published phase I/II study, IL-4 was administered to CLL patients. In most of them, IL-4 promoted an increase in the number of circulating CLL lymphocytes (38). In accordance with most of the in vitro data, the in vivo administration of IL-4 may thus induce a stimulatory or anti-apoptotic effect on the leukemic CLL clone.
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