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Similar to matrix metalloproteinases (MMP-9/-2), IL-18 was overexpressed in some hematologic malignancies such as acute myeloid leukemia (AML), which is associated with a poor clinical outcome. To establish a possible functional relationship between IL-18 and MMPs in myeloid leukemia, we used semi-quantitative PCR and zymographic analysis to examine whether IL-18 stimulates human myeloid leukemia cell line HL-60 to produce MMPs and/or specific tissue inhibitors (TIMPs), and to degrade extracellular matrix (ECM) gel in vitro. In the ECM invasion assay IL-18 significantly up-regulated transmigration of HL-60 cells, which in turn was inhibited by a synthetic MMP inhibitor: O-phenanthroline (o-PE), anti-MMP-9, anti-MMP-2 as well as anti-IL-18 monoclonal antibody (McAb), respectively, suggesting that induction of gelatinases by IL-18 leads to ECM degradation by these cells. Moreover, IL-18 could significantly increase MMP-9 but not MMP-2 production at both mRNA and/or protein level, slightly up-regulate TIMP-1 mRNA, and clearly induce TIMP-2 mRNA secretion. We postulate that IL-18 may in part play a role in the clinical aggressiveness of human myeloid leukemia by stimulating MMP-9 production. [Copyright &y& Elsevier]

Abstract: The P2X7 nucleotide receptor is an adenosine 5′-triphosphate (ATP)-gated ion channel, which induces cation channel opening imparting significant permeability to Ca2+, and is widely expressed in cells of hematopoietic origin. Our previous report showed that P2X7-mediated calcium response was absent in three Epstein-Barr virus (EBV)-positive and P2X7 positive cell lines. In this report, we detected the cell surface ATPase activity, which contributes to the hydrolysis of extracellular ATP, and the expression of CD39, which is the main source of ATPase on hematopoietic cells, in these cell lines. Then, we tried to restore the P2X7-mediated calcium response in LCL-H and J6-1 cells by either increasing the concentration of agonist or suppressing the ATPase activity by βγMeATP, a synthetic poorly metabolizable ATP analogue. The results showed that LCL-H and J6-1 cells had higher levels of ATPase activity and CD39 expression. The treatment of 300μM βγMeATP efficiently inhibited the ATPase activity on LCL-H and J6-1 cells. Both elevation of agonist concentration (10mM ATP or 1mM BzATP) and pretreatment with 300μM βγMeATP followed by stimulation with normal concentration of agonists (1mM ATP or 0.1mM BzATP) could cause P2X7-mediated calcium response in LCL-H but neither in J6-1 cells. These results suggested that multiple mechanisms contributed to the loss of the P2X7-mediated calcium response. CD39-associated high ATPase activity contributed to the loss of the P2X7-mediated calcium response in LCL-H cells, while additional mechanism(s) existed in J6-1 cells. [Copyright &y& Elsevier]

Little is known about the clinical significance of interleukin (IL)-18, a novel immunoregulatory cytokine, in acute myeloid leukemia (AML). Using reverse transcriptase polymerase chain reaction (RT-PCR) analysis, levels of IL-18 mRNA were assessed in bone marrow mononuclear cells (BMMC) from 47 adult patients with de novo or CR AML in order to explore the clinical significance of IL-18. The relationship between expression levels and the established prognostic factors such as age, cytogenetic aberrations, CD34 expression and FAB subtypes was investigated. Either disease status, age or CD34 expression were found to significantly correlate with the expression of IL-18. With respect to FAB cytotypes, expression of IL-18 gene in M4/M5 (n=15) was statistically higher than that in other subtypes (n=32, P<0.001). Moreover, a significant difference in IL-18 gene expression was obtained between the high risk group and the intermediate risk group (0.5627 versus 0.3111, P=0.038). In addition, a relationship between IL-18 expression of BMMC and initial white blood cell (WBC) was clearly demonstrated by a statistical analysis (r=0.806, P<0.001). These observations suggest that IL-18 gene over-expression might reflect the convergence of several important unfavorable prognostic factors in AML. [Copyright &y& Elsevier]