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Role of the RANKL/RANK system in the induction of interleukin‐8 (IL‐8) in B chronic lymphocytic leukemia (B‐CLL) cells

B chronic lymphocytic leukemia (B‐CLL) cells express several members of the tumor necrosis factor (TNF) family, such as CD40L, CD30L, and TRAIL. By using the cDNA microarray technology, B‐CLL samples were found to overexpress receptor activator of nuclear factor kB (NF‐kB) ligand (RANKL), as compared to normal CD19+ B cells. These findings were validated at the protein level by Western blot and flow cytometry analyses. Moreover, unlike primary normal B cells, leukemic B‐CLL cells showed surface expression of RANK, the cognate transmembrane receptor of RANKL. When added in vitro to B‐CLL cultures, either alone or in association with chlorambucil or fludarabine, recombinant RANKL did not significantly modulate cell viability, and it minimally affected the IL‐8 expression/release. On the other hand, treatment with RANK‐Fc chimera potently upregulated the release of IL‐8 in the B‐CLL culture supernatants, suggesting involvement of reverse signaling through transmembrane RANKL in IL‐8 induction. In turn, exposure of B‐CLL cells to recombinant IL‐8 significantly decreased spontaneous apoptosis as well as chlorambucil‐ and fludarabine‐mediated cytoxicity in B‐CLL cells. Since IL‐8 has been implicated in progression of B‐CLL disease, our findings suggest that, by upregulating IL‐8, the RANKL/RANK system may contribute to the pathogenesis of B‐CLL. J. Cell. Physiol. 207: 158–164, 2006. © 2005 Wiley‐Liss, Inc.