Interleukin10

IL-10 is a cytokine produced by type 2 helper T-cells, as well as by monocytes and B-lympho-cytes, with strong immunosuppressive effects via inhibition of Thl-type cytokines, including IFN-y and IL-2 (60-62). It has a potent stimulating effect on B-cells and is capable of inducing proliferation and differentiation (63).

The role of IL-10 in the pathogenesis and clinical course of CLL is one of the more controversial within the cytokines potentially connected with this disease (Fig. 1). Leukemic CLL lymphocytes express both the IL-10 mRNA and its receptor (64,65); thus, an autocrine role in sustaining the leukemic clone survival has been proposed for this cytokine. As a matter of fact, IL-10 has been reported to inhibit proliferation and to both inhibit and induce apoptosis of CLL lymphocytes (66-68). In the study by Fluckiger et al. (67), IL-10 was found to be capable of inducing CLL cells to die from apoptosis with a concomitant decrease in bcl-2 protein levels. In contrast, other authors reported a spontaneous release of IL-10 by CLL cells and a survival effect through inhibition of apoptotic cell death (69). Consistent with the latter data, Jurlander and collegues (70) also found that IL-10 could prolong survival of CLL cells, with a pattern of STAT protein phosphorylation similar to that induced through the receptors for IFN-a and IFN-y, proteins known to inhibit apoptosis in CLL cells. More suggestions come from a murine model of CLL, the B-1 malignant clones in NZB mice. In this spontaneously arising malignancy, IL-10 acts as an autocrine growth factor, and its gene expression levels increase with disease progression (71). The role of IL-10 in B-1 cells, investigated by means of antisense IL-10 oligonucleotides, would lie in its ability to inhibit apoptosis induction through the maintenance of sustainable cell cycle progression (72).

Just as equivocal are literature data on the in vivo production of IL-10: the ability to express IL-10 mRNA by CLL leukemic cells has been found to be associated with stable disease and to be lost in patients with progressive CLL (65), whereas serum levels seem to follow an inverse pattern. CLL patients in more advanced stages of their disease show higher levels of IL-10 compared with normal controls and with patients in Rai stages 0-II (73,74). Moreover, in the recent report by Fayad et al. (50), elevated levels of IL-10 were an independent prognostic factor for survival, directly correlated with unfavorable features such as advanced Rai stage, older age, and previous treatment. Based on these data, the source of IL-10 in CLL might be the polyclonal normal cells rather than the leukemic clone.

ELEVATED LEVELS OF IL-10 IN THESERUM. PROGNOSTIC FACTOR?

Fig. 1. Controversial role of interleukin-10 (IL-10) in CLL. The ability of IL-10 to either inhibit or induce apoptosis of CLL lymphocytes needs to be further investigated, as well as the suggested prognostic role of IL-10 serum levels in CLL patients, since contrasting data have been reported in the literature. In addition, IL-10 may exert a direct inhibitory effect on the antigen-presenting cell compartment and induce predominantly Th-2 type T-cell responses. DC, dendritic cell.

ELEVATED LEVELS OF IL-10 IN THESERUM. PROGNOSTIC FACTOR?

Fig. 1. Controversial role of interleukin-10 (IL-10) in CLL. The ability of IL-10 to either inhibit or induce apoptosis of CLL lymphocytes needs to be further investigated, as well as the suggested prognostic role of IL-10 serum levels in CLL patients, since contrasting data have been reported in the literature. In addition, IL-10 may exert a direct inhibitory effect on the antigen-presenting cell compartment and induce predominantly Th-2 type T-cell responses. DC, dendritic cell.

Finally, the elevated levels of IL-10 in CLL may also influence the growth and survival of the leukemic clone through its effects on the residual accessory compartment. Indeed, IL-10 production could represent a factor that affects the shift toward a Th-2-type response and the overexpression of type 2 cytokines reported in CLL patients (34,36). In addition, IL-10 exerts a direct inhibitory effect on the antigen-presenting cell compartment and is capable of inducing a downmodulation of MHC class II and B7 expression of peripheral blood dendritic cells. Further investigations will clarify whether these mechanisms are effective in CLL patients.

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