Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Carrier Proteins / pharmacology
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Cell Survival / drug effects
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Chlorambucil / pharmacology
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Flow Cytometry
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Gene Expression / genetics
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Glycoproteins / genetics
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Glycoproteins / metabolism*
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Humans
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Immunoglobulin G / genetics
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Interleukin-1 / pharmacology
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Interleukin-8 / genetics
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Interleukin-8 / metabolism*
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Interleukin-8 / pharmacology
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / pharmacology
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Oligonucleotide Array Sequence Analysis
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Up-Regulation / genetics
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Vidarabine / analogs & derivatives
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Vidarabine / pharmacology
Substances
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Antineoplastic Agents
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Carrier Proteins
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Glycoproteins
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Immunoglobulin G
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Interleukin-1
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Interleukin-8
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Membrane Glycoproteins
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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TNFRSF10A protein, human
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TNFRSF11A protein, human
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TNFRSF11B protein, human
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TNFSF11 protein, human
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Chlorambucil
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Vidarabine
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fludarabine