IL-8/NAP-1 is a member of the proinflammatory supergene family with potent and specific neutrophil activation and chemoattractant properties (52-54). IL-8 is constitutively expressed by CLL leukemic cells and released in the serum, contributing through an autocrine pathway to the process of cell accumulation characteristic ofthis disease (55,56). In fact, the addition of IL-8 at doses comparable to the levels released constitutively by CLL cells can prolong their survival, whereas endogenous IL-8 neutralization by anti-IL-8 antibodies is capable of inducing the in vitro death of CLL cells. Moreover, IL-8 has the ability to upmodulate IL-8 mRNA in CLL B-lymphocytes (57).
The survival activity of IL-8 on CLL cells is not based on its ability to stimulate proliferation, but rather on its ability to inhibit apoptosis in CLL leukemic cells. In fact, IL-8 belongs to the number of cytokines that exert their anti-apoptotic role through a bcl-2-dependent pathway. Circulating levels of IL-8 have been found to parallel the mRNA expression of bcl-2 by CLL cells (58), and this cytokine is experimentally capable of increasing bcl-2 expression in CLL lymphocytes (57).
Beside its ability to sustain the survival of the leukemic clone, IL-8 may also have a role in the pathogenesis of the disease as a potential mediator of CLL cell motility, as discussed below in the chemokine section (Subheading 4.2.). Taken together, these findings may justify the prognostic role proposed for this cytokine in CLL. Clinically, stage A patients with levels of IL-8 above the median value were shown to be more likely to progress to a more advanced clinical stage than those with levels below the median value (58). With a different and more sophisticated approach, the IL-8 coding gene was identified as one of the genes whose expression levels significantly correlated with patient survival or clinical stage in a recent microarray gene expression analysis of peripheral blood samples from 54 CLL patients (59).
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