UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukaemia Inhibitory Factor (LIF) is a polyfunctional cytokine, that belongs to the family of haemopoietic growth factors. LIF plays a role in growth-promotion and differentiation, regulates calcium and bone metabolism, induces acute phase proteins and causes cachexia in organisms with neoplastic disorders. LIF is also to be found in normal skin, where it may be involved in the differentiation process of keratinocytes. In addition, recent data in medical literature indicates that LIF is engaged in the pathogenesis of some skin disorders as well. It has been clearly demonstrated that LIF may act as a proinflammatory cytokine. In allergic contact dermatitis, the expression of LIF mRNA is augmented to a significant degree, indicating that LIF may play a role in the early phase of allergic contact dermatitis. LIF also plays an important role in psoriatic lesions. As the mechanism is not yet fully understood, however, it is hypothesized that the LIF function in psoriatic processes is solely connected with IL-8, as it is known that LIF is able to induce the release of IL-8. Also, some reports have suggested that LIF may also play a role in the carcinogenesis of the skin.
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PMID:The multifunctional role of leukaemia inhibitory factor in cutaneous biology. 1581 47

In this study, we examined how IL-8 induces leukocyte migration on major beta1 integrin ligands derived from the extracellular matrix protein fibronectin. We assessed individual contributions of signaling by IL-8 receptors by transfection of CXCR1 and CXCR2 into rat basophilic leukemia (RBL) cells and human monocytic THP-1 cells. CXCR1 expressing cells migrated on the fibronectin ligands for alpha4beta1 and alpha5beta1 integrins in response to IL-8, whereas CXCR2 expressing cells did not. RBL cells expressing the chimeric CXCR1 receptor containing the cytoplasmic tail of CXCR2 had greatly blunted migration, while cells expressing the CXCR2 chimera with the tail of CXCR1 had augmented migration. Last, inhibitors of p38 and JNK MAP kinases blocked IL-8-induced migration in CXCR1+ cells. We conclude that IL-8 stimulated beta1 integrin-mediated leukocyte migration on fibronectin through CXCR1 is dependent on the C-terminal cytoplasmic domain of CXCR1 and subsequent p38 and JNK MAPK signaling.
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PMID:The CXCR1 tail mediates beta1 integrin-dependent cell migration via MAP kinase signaling. 1589 7

Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.
Leukemia 2005 Oct
PMID:Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia. 1610 86

Indirubin, a purple vegetable dye, is a traditional Chinese medicine for myelocytic leukaemia. Indirubin inhibits cyclin-dependent protein kinases (CDKs) and is present in human urine and serum. When indirubin was present during the neutrophilic differentiation of human myelocytic leukaemia HL-60 cells, it augmented superoxide production triggered by opsonized zymosan (OZ) by the terminally differentiated HL-60 cells. It also augmented the calcium response to OZ stimulation, and HL-60 cell chemotaxis evoked by interleukin-8 (IL-8, CXCL8) and formylpeptide. In addition, indirubin induced marked IL-8 release by the cells during differentiation and the cells differentiated with indirubin had typical neutrophilic properties, deformed nuclei and granules. Use of stable cloned HL-60 cells that contained a reporter vector for monitoring the activity of the transcription factor PU.1, which acts specifically at the stage of promyelocyte differentiation into neutrophils and monocytes, revealed that indirubin has a potent promoting activity on intracellular PU.1. Indirubin enhanced the expression of typical neutrophil proteins, including granulocyte-colony stimulating factor receptor, the beta2-integrin subunit CD18, the NADPH-oxidase subunit p47phox, and the IL-8 receptor CXCR1, all are controlled by PU.1. Indirubin also inhibited CDK2-dependent phosphorylation of retinoblastoma protein during neutrophilic differentiation. These results suggest that indirubin augments the neutrophilic differentiation of human myelocytic leukaemia HL-60 cells through inhibition of CDK2 and activation of PU.1.
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PMID:Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL-60 cells. 1611 23

Oxidized low-density lipoproteins play important roles in the development of atherosclerosis and contain several lipid-derived, bioactive molecules which are believed to contribute to atherogenesis. Of these, some cholesterol oxidation products, referred to as oxysterols, are suspected to favor the formation of atherosclerotic plaques involving cytotoxic, pro-oxidant and pro-inflammatory processes. Ten commonly occurring oxysterols (7alpha-, 7beta-hydroxycholesterol, 7-ketocholesterol, 19-hydroxycholesterol, cholesterol-5alpha,6alpha-epoxide, cholesterol-5beta,6beta-epoxide, 22R-, 22S-, 25-, and 27-hydroxycholesterol) were studied for both their cytotoxicity and their ability to induce superoxide anion production (O2*-) and IL-8 secretion in U937 human promonocytic leukemia cells. Cytotoxic effects (phosphatidylserine externalization, loss of mitochondrial potential, increased permeability to propidium iodide, and occurrence of cells with swollen, fragmented and/or condensed nuclei) were only identified with 7beta-hydroxycholesterol, 7-ketocholesterol and cholesterol-5beta,6beta-epoxide, which also induce lysosomal destabilization associated or not associated with the formation of monodansylcadaverine-positive cytoplasmic structures. No relationship between oxysterol-induced cytotoxicity and HMG-CoA reductase activity was found. In addition, the highest O2*- overproduction quantified with hydroethidine was identified with 7beta-hydroxycholesterol, 7-ketocholesterol and cholesterol-5beta,6beta-epoxide, with cholesterol-5alpha, 6alpha-epoxide and 25-hydroxycholesterol. The highest capacity to simultaneously stimulate IL-8 secretion (quantified by ELISA and by using a multiplexed, particle-based flow cytometric assay) and enhance IL-8 mRNA levels (determined by RT-PCR) was observed with 7beta-hydroxycholesterol and 25-hydroxycholesterol. None of the effects observed for the oxysterols were detected for cholesterol. Therefore, oxysterols may have cytotoxic, oxidative, and/or inflammatory effects, or none whatsoever.
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PMID:Comparison of the cytotoxic, pro-oxidant and pro-inflammatory characteristics of different oxysterols. 1614 84

Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is characterized as an important enzyme for protecting cells from oxidative stress-induced apoptosis and regulating the production of leukotrienes and prostanoids in cells overexpressing PHGPx. We studied whether the expression level of PHGPx fluctuates in polymorphonuclear leukocytes (PMNs) which were exposed to reactive oxygen species (ROS) and inflammatory cytokines at an inflammation site. Human peripheral PMNs up-regulated the expression level of PHGPx following culture with TNF-alpha, but not with IL-1beta, IL-8, and GRO. The up-regulated PHGPx expression was also observed in neutrophil-like cells that differentiated from the human leukemia cell line HL60 only after stimulation with TNF-alpha. However, macrophage-like differentiated HL60 cells and other cell lines, A498, ECV304, HeLa, U937, and HEK293, showed no increase in the PHGPx expression. This up-regulation of PHGPx was inhibited by treatment with the anti-oxidants, pyrrolidine dithiocarbamate, and N-acetyl-L-cysteine, and by inhibitors of NFkappaB and Src kinases. The stimulation of neutrophil-like differentiated HL60 cells with TNF-alpha induced activation of NFkappaB and c-Src kinase, and the activation was attenuated by treatment with the anti-oxidants. Up-regulation in neutrophil-like HL60 cells was also observed following exposure to H(2)O(2). These results indicate that activation of NFkappaB and/or Src kinases through ROS signaling may be involved in the up-regulation of the PHGPx in human PMNs stimulated by TNF-alpha.
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PMID:Induction of phospholipid hydroperoxide glutathione peroxidase in human polymorphonuclear neutrophils and HL60 cells stimulated with TNF-alpha. 1622 6

Protein farnesyltransferase inhibitors (FTIs) have shown clinical responses in hematologic malignancies, but the mechanisms are unclear. To better understand potential mechanisms of action, we have studied effects of the FTI tipifarnib on inflammatory responses in vitro and in vivo. In a human leukemia cell line THP-1, tipifarnib inhibited lipopolysaccharide (LPS)-induced transcription of chemokines [monocyte chemotactic protein (MCP)-1 and MCP-2], cytokines [interleukin (IL)-1beta, IL-6, and interferon (IFN)beta], signaling molecules (MyD88 and STAT-1), proteases [matrix metalloproteinase (MMP-9)], and receptors (urokinase receptor). Tipifarnib also inhibited LPS-induced secretion of MMP-9, IL-6, MCP-1, and IL-1beta in THP-1 cells. In primary human peripheral blood mononuclear cells, dose-dependent inhibition of LPS-induced tumor necrosis factor (TNF)-alpha, IL-6, MCP-1, and IL-1beta by tipifarnib was observed with no evidence of cytotoxicity. Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pretreatment with tipifarnib resulted in significant inhibition of TNF-alpha, IL-6, MCP-1, IL-1beta, and MIP-1alpha production. Tipifarnib had no effect in vitro or in vivo on LPS-induced IL-8. Studies in THP-1 cells to address potential mechanism(s) showed that tipifarnib partially inhibited LPS-induced p38 phosphorylation. Tipifarnib significantly inhibited inhibitory subunit of nuclear factor-kappaB (NF-kappaB) (IkappaB)-alpha degradation and p65 nuclear translocation induced by LPS, but not by tumor necrosis factor-alpha, IL-1alpha, or toll-like receptor (TLR)2 ligand, suggesting that the target for inhibition of NF-kappaB activation was exclusive to the LPS/TLR4 signal pathway. The extent of IkappaB-alpha degradation inhibition did not correlate with inhibition of Ras farnesylation, indicating that Ras was not the target for the observed anti-inflammatory activity of tipifarnib. Our findings differ from those for other FTIs, which may have relevance for their dissimilar activity in specific tumor repertoires.
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PMID:Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor tipifarnib. 1635 5

Drug reactions can be considered as being either predictable or unpredictable. A predictable reaction would be the result of the pharmacologic action of the medication. An unpredictable reaction might be idiosyncratic, might be drug intolerance, or might have or imply an immunologic basis, such as being IgE mediated. Immediate reactions that are not IgE mediated can be considered as pseudoallergic (non-IgE-mediated mast cell activation). This review will discuss allergic and immunologic reactions to immunomodulators, penicillins and cephalosporins, sulfonamides, aspirin, and nonselective nonsteroidal anti-inflammatory drugs and consider the serious drug-related conditions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The field of drug "allergy" has expanded to include adverse reactions associated with immunosuppressive medications, anticytokine therapies, and mAbs. The cytokine release reaction that occurs with anti-CD20 antibody infusions in patients with leukemia and white blood cell counts of greater than 50 x 10(9)/L is associated with high concentrations of TNF, IL-6, and IL-8. Because of the findings of fever, dyspnea, rigors, and hypotension, this reaction resembles the Jarisch-Herxheimer reaction that occurs 60 to 90 minutes after penicillin administration in patients with secondary syphilis. Furthermore, the care of the patient with penicillin allergy has been made more difficult in the absence of the major determinant, penicilloyl-polylysine, in that from 34% to 84% of patients who have positive skin test reactions to penicillin have exclusively positive reactions to the major determinant. SJS and TEN typically are caused by medications within 1 to 8 weeks of initiation of therapy. Evidence for death of the keratinocytes through (1) drug-specific cytotoxicity with the perforin-granzyme B-mediated killing and (2) activation of Fas on keratinocytes have provided explanations for the sloughing of skin. Unfortunately, intravenous immunoglobulin therapy for SJS and TEN has been disappointing.
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PMID:8. Drug allergy. 1645 48

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.
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PMID:Effects of interferon gamma on native human acute myelogenous leukaemia cells. 1661 97

Mycoplasma can establish latent infections and are associated with arthritis, leukemia, and chronic lung disease. We developed an experimental model in which lung cells are deliberately infected with Mycoplasma fermentans. Human lung fibroblasts (HLF) were exposed to live M. fermentans and immune-modulating cytokine release was assessed with and without known inducers of cytokine production. M. fermentans increased IL-6, IL-8/CXCL8, MCP-1/CCL2, and Gro-alpha/CXCL1 production. M. fermentans interacted with TNF-beta to release more IL-6, CXCL8, and CXCL1 than predicted by the responses to either stimulus alone. The effects of live infection were recapitulated by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2- and receptor-6-specific ligand. The synergistic effect of combined stimuli was more pronounced with prolonged incubations. Preexposure to TNF-beta sensitized the cells to subsequent MALP-2 challenge, but preexposure to MALP-2 did not alter the IL-6 response to TNF-beta. Exposure to M. fermentans or MALP-2 did not enhance nuclear localization, DNA binding, or transcriptional activity of NF-kappaB and did not modulate early NF-kappaB activation in response to TNF-beta. Application of specific inhibitors of various MAPKs suggested that p38 and JNK/stress-activated protein kinase were involved in early IL-6 release after exposure to TNF-beta and M. fermentans, respectively. The combined response to M. fermentans and TNF-beta, however, was uniquely sensitive to delayed application of SP-600125, suggesting that JNK/stress-activated protein kinase contributes to the amplification of IL-6 release. Thus M. fermentans interacts with stimuli such as TNF-beta to amplify lung cell production of immune-modulating cytokines. The mechanisms accounting for this interaction can now be dissected with the use of this in vitro model.
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PMID:Mycoplasma fermentans and TNF-beta interact to amplify immune-modulating cytokines in human lung fibroblasts. 1675 Dec 26

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