interleukin-8 and Leukemia-Lymphoma--Adult-T-Cell

Cytokines released in the bone marrow and thymic microenvironments play a key role in the growth of T-cell acute lymphoblastic leukemia. Among such cytokines, interleukin-8 is highly expressed in T-cell acute lymphoblastic leukemia cells refractory to chemotherapy. In this study we explored whether bone marrow stromal cells can regulate IL-8 expression in T-cell acute lymphoblastic leukemia and investigated the role of the stromal CXCL12 chemokine in this event. We also investigated the roles of the nuclear factor-kappaB and Jun-N-terminal kinase (JNK)/activating protein (AP)-1 signaling pathways, which contribute to regulate interleukin-8 production in some cells.. We analyzed the expression of interleukin-8 in primary cells from ten adult patients with T-cell acute lymphoblastic leukemia when these cells were cultured with bone marrow stromal cells or stimulated with exogenous CXCL12. Interleukin-8 mRNA was analyzed by a colorimetric assay. Cytokine production was assayed by cytometric antibody array and flow cytometry. Nuclear factor-kappaB and JNK/AP-1 activation was investigated by using specific inhibitors of these pathways, immunoblotting, electrophoretic mobility-shift assay and cell transfection assays.. Bone marrow stromal cells upregulated interleukin-8 mRNA in T-cell acute lymphoblastic leukemia cells through the activity of CXCR4, the CXCL12 receptor, as assessed by the use of neutralizing antibodies. Exogenous CXCL12 induced a significant increase in the production of IL-8 mRNA and protein in all T-cell acute lymphoblastic leukemia cases. We showed that CXCL12 activates the nuclear factor-kappaB and JNK/AP-1 pathways, and that these events are required for increased expression of interleukin-8. Furthermore, the nuclear factor-kappaB and AP-1 elements of the interleukin-8 promoter are necessary for both constitutive and CXCL12-induced interleukin-8 expression.. Interleukin-8 is physiologically regulated by the CXCL12/CXCR4 axis and the nuclear factor-kappaB and JNK/AP-1 pathways are required for interleukin-8 expression in T-cell acute lymphoblastic leukemia. We propose that, by upregulating interleukin-8, the bone marrow microenvironment and the CXCL12/CXCR4 axis may play a role in the pathogenesis of T-cell acute lymphoblastic leukemia.

Topics: Adult; Bone Marrow Cells; Chemokine CXCL12; Clinical Trials as Topic; Gene Expression Regulation, Leukemic; Humans; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; Leukemia-Lymphoma, Adult T-Cell; Multicenter Studies as Topic; Neoplasm Proteins; NF-kappa B; Receptors, CXCR4; Recombinant Fusion Proteins; RNA, Messenger; RNA, Neoplasm; Stromal Cells; Transcription Factor AP-1; Transfection; Up-Regulation

Adult T cell leukemia (ATL) cells show a mature helper-inducer T cell phenotype and are thought to secrete many kinds of cytokines in vivo, complicating the clinical features in these patients. In an attempt to specify the cytokines produced by ATL cells, we measured the cytokine concentration in the culture supernatants of three ATL cell lines, all of which were confirmed to be true peripheral blood ATL cell in origin. All these cell lines showed the same cytokine production profile, secreting IL1-alpha, IL1-beta, LD78(MIP-l alpha), TNF-alpha, IFN-gamma, and GM-CSF, but not secreting IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1 Ra), IL-4, IFN-alpha, and G-CSF irrespective of the stimulatory agents used. Such limited cytokine production may indicate the specific origin of ATL cells within the helper-inducer T cell subtypes. Moreover, these results explain some of the unusual clinical features of ATL patients.

Topics: Adult; Chemokine CCL4; Culture Media, Conditioned; Cytokines; Granulocyte Colony-Stimulating Factor; Humans; Interferon-gamma; Interleukin-8; Interleukins; Leukemia-Lymphoma, Adult T-Cell; Macrophage Inflammatory Proteins; Neoplastic Stem Cells; Th1 Cells; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha