interleukin-8 and Lymphoma--Large-Cell--Anaplastic

Topics: Adult; Humans; Interleukin-8; Ki-1 Antigen; Lymphocytes; Lymphoma, Large-Cell, Anaplastic; Male; Neoplasm Regression, Spontaneous; Neutrophils; Skin Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Diagnostic Errors; Fatal Outcome; Humans; Immunohistochemistry; Interleukin-8; Lymphoma, Large-Cell, Anaplastic; Male; Middle Aged; Neutrophils; Predictive Value of Tests; Time Factors; Treatment Outcome

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

CD30 is a member of the tumor necrosis factor superfamily. In this study, we examined the effect of four anti-CD30 (aCD30) antibodies (Abs) on CD30-positive anaplastic large cell lymphoma-derived cell line, Ki-JK. The aCD30 Abs suppressed [3H]thymidine (TdR) incorporation. With a TdT mediated dUTP-biotin nick end labeling method, apoptosis was detected in Ki-JK cells at day 5 after the addition of aCD30 Ab to the culture. Genistein, an inhibitor of protein tyrosine kinase, had no effect on aCD30 Ab-induced apoptosis. The aCD30 Ab simultaneously induced interleukin-8 (IL-8) secretion in the Ki-JK cells. In culture of the Ki-JK cells with aCD30 Ab for 5 days, the IL-8 concentration of the cell free-supernatant increased to 240 +/- 16 pg/ml, though the concentration was < 12.5 pg/ml without aCD30 Ab. In combination with aCD30 Ab, genistein decreased the concentration of IL-8 in day 5 supernatants. Although, doxorubicin and herbimycin-A suppressed [3H]TdR incorporation and induced apoptosis in the Ki-JK cells, they did not induce IL-8 secretion. Only aCD30 Ab-induced apoptosis was accompanied by IL-8 secretion. IL-8 mRNA was not detected in the Ki-JK cells by reverse transcription-polymerase chain reaction assay. IL-8 mRNA was detected 5 days after adding aCD30 Ab to the culture.

Topics: Antibodies; Apoptosis; Humans; Interleukin-8; Ki-1 Antigen; Lymphoma, Large-Cell, Anaplastic; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured