Elevated Levels of IL-17, MIP-1 β, MIG and ITAC in B-Cell Chronic Lymphocytic Leukemia: Correlation with Prognostic Markers.

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B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the progressive accumulation of mature B cells. The growth and accumulation of B-CLL cells requires survival and migratory signals from endogenously produced cytokines and chemokines, many of which are supplied by stromal cells. In this comparative study we analyzed the expression, as a function of B-CLL disease, of a set of inflammatory and immune cytokines and chemokines known to regulate the growth, survival and/or trafficking of B cells. Serum cytokines were measured in 87 B-CLL patients and in 32 healthy subjects using a combination of multiplex cytokine bead and protein array technologies. A subset of cytokines and chemokines were found to be significantly elevated in serum from B-CLL patients as compared to healthy age-matched controls: IL-17 (p<0.01), MIP-1β (p<0.001), MIP-1α (p<0.01), IL-6 (p<0.05), IL-8 (p<0.001), IL-10 (p<0.001), IL-12 (p<0.05), MIG (p<0.01), and ITAC (p<0.001). Serum levels of IL-1β, IL-1α, IL-2, IL-4, IL-5, IL-12, IL-13, IL-15, TNFα, IFNγ, IFNα, GM-CSF, Eotaxin, and MCP-1 were not significantly different in B-CLL patients as compared to healthy age-matched controls. Previous studies have reported elevated levels of IL-6, IL-8, IL-10, and MIG in B-CLL, and these molecules may contribute anti-apoptotic and growth-promoting signals that allow the expansion of B-CLL cells. IL-17 is known to promote angiogenesis and induce stromal cell expression of cytokines and chemokines that support B-CLL survival, suggesting potential mechanisms whereby this cytokine may impact on B-CLL biology. MIG and ITAC are ligands for CXCR3, a chemokine receptor expressed on B-CLL cells. These chemokines positively affect the responsiveness of pDC to the homing chemokine, SDF-1, raising the possibility that their elevation in B-CLL may lead to increased responsiveness of B-CLL cells to SDF-1, a stromal factor that enhances their survival. MIP-1α and MIP-1β are inflammatory chemokines that regulate cell recruitment and activation. Interestingly, MIP-1α and MIP-1β trigger stromal cells to produce RANKL, which has recently been suggested to contribute to B-CLL pathogenesis by triggering production of IL-8. B-CLL patients divide into populations that present with (a) stable disease and favorable prognostics including mutated VH and low CD38 expression, and (b) progressive disease with poor prognostics including unmutated VH and high CD38. When serum cytokines were analyzed as a function of select prognostic indicators discrete differences were observed. IL-8 levels correlated with mutated VH, IL-17 and IL-6 levels correlated with unmutated VH, and MIG, IP-10 and ITAC levels correlated with high CD38 expression. MIP-1α and MIP-1β levels differed significantly from controls irrespective of mutational status or CD38 expression. The correlation of IL-17, which in addition to its stromal activating properties is known to promote angiogenesis, with unmutated VH suggests a potential role for this cytokine in mediating the increased angiogenic phenotype that has been observed in poor prognosis CLL.