IL-6, a pleiotropic cytokine produced by a variety of cell types, is a well-characterized B-cell growth and differentiation factor, known to be essential for normal B-cell development and megakaryocyte maturation, and involved in the pathogenesis of several B-cell malignancies (39-41).
In contrast with what is observed in other B-cell neoplasms, IL-6 does not induce CLL cell proliferation in vitro (42-44), and, when administered in vivo in an attempt to increase sensitivity to chemotherapy, no growth-stimulatory effects have been observed (45). Nevertheless, this cytokine may have a role in sustaining the survival of the leukemic clone, as suggested by its effects on apoptosis of CLL cells and by the relationship between IL-6 serum levels and disease progression. With regard to the anti-apoptotic activity of IL-6 on CLL leukemic cells, the results are controversial: some researchers have found no effect, whereas others have described the inhibition of apoptosis by IL-6 (11,19,30,43). The mechanism proposed for this effect would be a delay in downregulation of bcl-2 in vitro (32). Recently, the anti-apoptotic activity of IL-6 has been ascribed to the dimeric, but not monomeric, form of this cytokine (46). In the report by Moreno et al. (46), although both the monomeric and dimeric forms of IL-6 bound IL-6R with comparable affinity, only the latter was capable of prolonging the survival of CLL lymphocytes in vitro. Moreover, in the same paper, the authors identify dimeric IL-6 as the soluble factor responsible for the anti-apoptotic effect exerted by endothelial cells on CLL B-lymphocytes in vitro. This cytokine, then, would be one of the soluble agents that mediate the interactions between stromal cells and CLL lymphocytes, a network that growing evidence indicates as pivotal in supporting the survival of the leukemic clone in vivo (47,48).
Serum levels of IL-6 have been found to be elevated in CLL patients compared with normal controls (13,22,43). Although CLL leukemic cells are known to produce a biologically active IL-6 protein, the non-neoplastic compartment could also be a source of IL-6 in CLL (49). A correlation between serum IL-6 levels and clinical features and survival has been recently described (50). Elevated IL-6 levels correlated with unfavorable features, such as advanced Rai stage, older age, and previous treatment, and patients with elevated serum IL-6 levels had a worse survival. Other groups have reported similar results, but it should be recalled that a reduced ability to produce IL-6 in CLL cells from patients with advanced disease has also been described (13,51).
As is the case with several cytokines in CLL, the mechanisms and modalities that influence the effects of IL-6 in vivo need to be further elucidated to obtain a more precise picture of the role of this cytokine in the pathogenesis of the disease.
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