interleukin-8 and Leukemic-Infiltration

Anaplastic large-cell lymphomas (ALCLs) bearing the t(2;5) translocation (ALK(+)ALCLs) are frequently characterized by skin colonization and associated with a poor prognosis. Using conditional transgenic models of anaplastic lymphoma kinase-positive (ALK(+)) lymphomas and human ALK(+)ALCL cell lines, in the present study, we show that high-mobility-group box-1 (HMGB-1), a proinflammatory cytokine, is released by ALK(+) cells, and demonstrate extracellular HMGB-1-stimulated secretion of the IL-8 chemokine by HaCaT keratinocytes through the involvement of MMP-9, PAR-2, and the NF-κB pathway. Furthermore, we demonstrate that, in vitro, IL-8 is able to induce the invasiveness of ALK(+) cells, which express the IL-8 receptors CXCR1 and CXCR2. In vitro and in vivo, HMGB-1 inhibition achieved by glycyrrhizin treatment led to a drastic reduction in ALK(+) cell invasiveness. The pathophysiological relevance of our observations was confirmed by demonstrating that the HMGB-1 and IL-8 receptors are expressed in ALK(+)ALCL biopsies. We have also shown that IL-8 secretion is correlated with leukemic dissemination of ALK(+) cells in a significant number of patients. The results of the present study demonstrate for the first time a relationship among the pro-inflammatory mediators HMGB-1, MMP-9, PAR-2, and IL-8. We propose that these mediators create a premetastatic niche within the skin, thereby participating in ALK(+) lymphoma epidermotropism.

Topics: Anaplastic Lymphoma Kinase; Animals; Cells, Cultured; Female; HMGB1 Protein; Humans; Interleukin-8; Keratinocytes; Leukemic Infiltration; Lymphoma, Large-Cell, Anaplastic; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, SCID; Mice, Transgenic; NF-kappa B; Receptor Protein-Tyrosine Kinases; Receptor, PAR-2; Signal Transduction; Skin; Stem Cell Niche

To evaluate the expression of interleukin 8 (IL-8) and its A, B type receptors (IL-8RA, IL-8RB) in acute leukemia (AL).. Plasma IL-8 concentrations in peripheral blood and IL-8R expressions on bone marrow mononuclear cell (MNC) membrane of 77 newly diagnosed AL patients were assayed by ELISA and FACS, respectively. IL-8 concentration in cerebral spinal fluid (CSF) of 15 AL patients in complete remission (CR) were kinetically measured.. Plasma IL-8 levels in newly diagnosed AL patients were increased. IL-8 levels were higher in AML than in ALL, in AML-M4, M5 were higher than in AML-M1-M3, and in B-ALL were higher than in T-ALL, respectively (P < 0.05). In ALL, CR rate in patients with IL-8 > 100 ng/L was lower than in those with IL-8 < or = 100 ng/L (P < 0.05). 36.36% of the patients were MNC IL-8R positive. Peripheral blood WBC and blasts amounts in IL-8R(+) group were significantly higher than IL-8R (-) group (P < 0.05). CSF IL-8 levels in CR patients were not different from newly diagnosed patients (P > 0.05) and were increased while central nervous system leukemia (CNSL) developed.. Detection of IL-8 and IL-8R might help to identify AL types and predict prognosis and the development of CNSL.

Topics: Adolescent; Adult; Aged; Central Nervous System; Female; Follow-Up Studies; Humans; Interleukin-8; Leukemia, Myeloid, Acute; Leukemic Infiltration; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Interleukin-8A; Receptors, Interleukin-8B