Tumor Necrosis Factora

TNF-a is a proinflammatory cytokine with heterogeneous activities, including immune modulation and regulation of tumor cell growth. In addition, it is also a growth factor for different normal cell populations, such as T- and B-lymphocytes (75,76).

TNF-a belongs to the group of multiple cytokines produced and released by CLL cells (77,78), which also express TNF-a receptors (79,80). Moreover, elevated serum levels of TNF-a are detectable in patients with CLL compared with normal controls, with a progressive increase in relation to the stage of disease (81,82). However, CLL patients also have elevated serum levels of soluble TNF-a receptor, and the latter appears to be more pronounced in advanced disease. In this situation, owing to the competitive effects of the soluble receptor form, the net effect of TNF-a on the surface of the neoplastic cells could be less relevant (80).

RELEASE OF OTHER

CLL cell

Fig. 2. TNF-a in CLL cell survival and cytokine loops. CLL cells spontaneously release TNF-a in vitro and respond to this cytokine, increasing their proliferative rate and suppressing apoptosis. The elevated serum levels of TNF-a in CLL patients may also induce the release of other cytokines and regulate the expression of IL-2 receptors (IL-2R).

RELEASE OF OTHER

IL-2

CLL cell

Fig. 2. TNF-a in CLL cell survival and cytokine loops. CLL cells spontaneously release TNF-a in vitro and respond to this cytokine, increasing their proliferative rate and suppressing apoptosis. The elevated serum levels of TNF-a in CLL patients may also induce the release of other cytokines and regulate the expression of IL-2 receptors (IL-2R).

The potential role of TNF-a as an autocrine growth factor in CLL is supported by observations reporting the ability of this cytokine to increase CLL B-lymphocyte proliferation (77,83) and to suppress apoptosis through a delay in downregulation of bcl-2 (32) (Fig. 2). It has to be noted, however, that other studies have not confirmed, or confirmed only partially, these data (11,78,79,84), so that the real role of TNF-a in influencing the proliferation and survival of CLL cells has still to be conclusively established. However, the elevated serum levels of TNF-a in CLL patients may play a pivotal role in regulating different cytokine pathways: the synthesis of IL-1 a, IL-1 P, and IL-6, as well as the expression of the p55 IL-2 receptor (79), is induced in CLL cells treated in vitro with TNF-a (85). Recently, TNF-a has also been shown to be capable of increasing CD20 expression significantly on CLL leukemic cells, a finding potentially exploitable in the treatment of CLL patients with the anti-CD20 monoclonal antibody (86,87).

IFN type I (a and P) and type II (y) were initially described as proteins capable of conferring resistance to viral infections in uninfected cells, but they have a broad variety of cellular effects, including regulation of cell proliferation and differentiation, as well as modulation of immune functions (88-90). The demonstration of its antineoplastic effects has led to the use of IFN-a as a therapeutic agent for different malignant diseases, including CLL (91,92).

The potential role of IFN-y as a clinically relevant anti-apoptotic cytokine in the pathogenesis of CLL has been suggested on the basis of experimental evidence. IFN-y inhibits programmed cell death and promotes survival of CLL cells in culture (93-95), an effect associated with a delay in

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