interleukin-8 and Leukemia--Lymphoid

T cell targeting immunotherapy is now considered a possible strategy in acute myelogenous leukaemia (AML), and IFNgamma release may then contribute to the antileukaemic effects. We investigated the effects of IFNgamma on native human AML cells. Normal T cells could be activated to release IFNgamma in the presence of AML cells. Furthermore, high levels of CD119 (IFNgamma receptor alpha chain) expression were observed for all 39 patients examined. Receptor expression was decreased after exposure to exogenous IFNgamma, and receptor ligation caused Stat1 phosphorylation but no phosphorylation of the alternative messengers Erk1/2. The effect of exogenous IFNgamma on AML blast proliferation was dependent on the local cytokine network and IFNgamma (1) inhibited proliferation in the presence of exogenous IL1beta, GM-CSF, G-CSF and SCF; (2) had divergent effects in the presence of IL3 and Flt3 (65 patients examined); (3) inhibited proliferation in the presence of endothelial cells but had divergent effects in the presence of fibroblasts, osteoblasts and normal stromal cells (65 patients examined). IFNgamma increased stress-induced (spontaneous) in vitro apoptosis as well as cytarabine-induced apoptosis only for a subset of patients. Furthermore, IFNgamma decreased the release of proangiogenic CXCL8 and increased the release of antiangiogenic CXCL9-11. We conclude that IFNgamma can be released in the presence of native human AML cells and affect AML cell proliferation, regulation of apoptosis and the balance between pro- and antiangiogenic chemokine release.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Cell Proliferation; Chemokine CXCL9; Chemokines, CXC; Cytarabine; Endothelium, Vascular; Female; Fibroblasts; Flow Cytometry; fms-Like Tyrosine Kinase 3; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interferon gamma Receptor; Interferon-gamma; Interleukin-1beta; Interleukin-3; Interleukin-8; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphocyte Activation; Male; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Osteoblasts; Phosphorylation; Receptors, Interferon; Signal Transduction; STAT1 Transcription Factor; Stromal Cells; T-Lymphocytes; Tumor Cells, Cultured

Interleukin-8 (IL-8), a member of the family of small inducible cytokines, is mainly known for its striking neutrophil-activating properties. Constitutive IL-8 production is negligible in normal leukocytes. We examined expression of IL-8 and its receptor in purified leukemic cells from patients with untreated acute myeloblastic leukemia (AML) and lymphoid leukemias. In the majority of cases (18 of 26 AML, 8 of 15 lymphoid leukemias), the cells constitutively expressed IL-8 mRNA transcripts. In all but 3 of these cases, IL-8 mRNA-expressing cells secreted biologically active IL-8 protein. Immunocytochemical analysis showed intracellular IL-8 (5% to 90% of total cells), demonstrating that the leukemic cells themselves rather than contaminants (monocytes or lymphocytes) were the source of IL-8. Ten of 25 AML samples expressed IL-8 receptor mRNA and, with 1 exception, the IL-8 receptor expressing cells also produced its ligand. In contrast, all lymphoid leukemias were negative. Furthermore, frequent coexpression of IL-8 and IL-1 beta transcripts was seen in both AML and lymphoid leukemia samples, whereas fewer cases coexpressed IL-8 and either macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. In leukemic cells expressing the IL-8 receptor, IL-8 induced cytosolic free calcium changes, indicating activation of the classical signaling pathway. These results suggest that IL-8 may have biologic activities in hematopoiesis.

Topics: Blotting, Southern; Cytokines; Humans; Interleukin-8; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Receptors, Interleukin; Receptors, Interleukin-8A; RNA, Messenger; Tumor Cells, Cultured

We have recently described the partial purification and characterization of a neutrophil migration inhibitory activity present in serum from patients with chronic lymphocytic leukaemia (CLL). This new lymphokine, the chemokinetic inhibitory factor (CIF), is produced by B-CLL cells. It is a heat-labile glycoprotein of an approximate molecular weight (m. w.) of 30000. In this extended investigation 64/89 CLL-patients had CIF in their serum. CLL serum diluted to a concentration of 0.02% gave significantly decreased chemokinetic activity, suggesting that CIF is potent at very low concentrations. 31/89 patients had increased infection propensity. Significantly more patients with CIF in serum had infections compared to the group with normal susceptibility to infections. The combination of low Ig levels and CIF in serum discriminated even better between the infection-prone and non-infection-prone patients. CIF in serum was not correlated to tumour cell mass - estimated by Rai clinical staging - tumour progression or deoxythymidine kinase, S-TK, an enzyme that may reflect proliferating cells. The existence of this new lymphokine in serum seems to contribute to the increased susceptibility to infections seen in CLL patients.

Topics: Adult; Aged; Chemotactic Factors; Disease Susceptibility; Dose-Response Relationship, Immunologic; Female; Hot Temperature; Humans; Immunoglobulins; Infections; Interleukin-8; Leukemia, Lymphoid; Lymphokines; Male; Middle Aged; Neoplasm Staging; Thymidine Kinase