Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD40 antigen is a member of the tumor necrosis factor receptor superfamily which interacts with its ligand and regulates the immune response via a dialogue between T-lymphocytes and antigen-presenting or tumor cells. Tumor triggering via CD40 exerts direct effects on cancer cells, which have mainly been investigated in terminally differentiated hematological malignancies such as low-grade lymphoma. We focused our attention on minimally differentiated acute myeloid leukemia (AML-M0), an aggressive hematological malignancy in which severe prognosis suggests the requirement for innovative therapeutic strategies. Here we demonstrate, for the first time to our knowledge, a CD40-triggered IL-8, RANTES and IL-12 secretion by leukemic cells. Supernatants from CD40-stimulated leukemia cells had chemoattractant effects on T-lymphocytes, natural killer cells and monocytes. Moreover, these supernatants, when complemented with low-dose IL-2, induced significant lymphokine-activated and natural killer cytotoxicity, leading to leukemia lysis both in allogenic HLA-matched and autologous settings. Stimulation of leukemia cells via CD40 could participate significantly to the anti-leukemia immune response by contributing to the development of an inflammatory response and to in situ cytotoxicity. Leukemia(2000) 14, 123-128.
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PMID:Acute myeloid leukaemia triggering via CD40 induces leukocyte chemoattraction and cytotoxicity against allogenic or autologous leukemic targets. 1063 87

GVHD is a significant cause of morbidity and mortality following allogeneic peripheral blood stem cell transplantation (AlloPBSC). CD34+ cell selection could reduce GVHD by negative selection of T cells. In an attempt to reduce the T cell content of alloPBSC we carried out a trial in which 11 patients with hematologic malignancies received alloPBSC from HLA-matched siblings following density gradient separation using an isotonic colloidal silica solution (BDS 60; Dendreon Corporation). Cyclosporine and methylprednisone were used for GVHD prophylaxis. The mean yield of CD34+ cells was 69 +/- 15.6% with a purity of 2.9 +/- 1.7%. The mean number of CD3+ cells infused was 1.0 +/- 1.2 x 107/kg, representing a 1.3 log depletion. A high risk of acute GVHD was observed: grade II-IV in 7/11 (64%) and grade III-IV GVHD in 5/11 (45%) patients. Nine of the 11 (82%) patients died with a median survival of 68 days. Cytokine expression in PBSC was compared pre and post processing. Interferon-gamma was detected only following density gradient separation while IL-8 expression increased 3- to 6-fold post processing. Therefore, processing with this device may augment production of pro-inflammatory cytokines. Bone Marrow Transplantation (2000) 25, 1223-1228.
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PMID:Allogeneic peripheral blood stem cell transplantation following CD34+ enrichment by density gradient separation. 1087 25

We studied intracellular cytokines in monocytes by flow cytometry from 28 patients with hematologic malignancies and solid tumors to analyze the role of monokines in the hematologic recovery phase for peripheral blood stem cell harvest. The patients were divided into three groups: the first group, A, had a documented infection; the second group, B, had fever of unknown origin; and the third group, C, was afebrile. We found an increase in intracellular IL-1alpha, IL-6, IL-8 and TNF-alpha positive monocytes as CD14 positive gated cells cultured with lipopolysaccharide in all groups, but no increase was found with medium only when cultured for 4 h. We also found an increase in intracellular IL-1a, IL-6, IL-8 and TNF-alpha positive monocytes cultured with autologous serum for 4 h, but only in group A. The rate of intracellular cytokine positive cells was higher in monocytes cultured with only autologous serum from group A patients compared to those cells from the other groups; the data concerning IL-1a, IL-6 and TNF-alpha reached statistical significance (P < 0.05). However, increasing intracellular cytokine levels in the control group of patients exhibiting only infectious disease were observed. Thus, it appear that pro-inflammatory intracellular cytokine levels in monocytes are only related to microbial infections.
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PMID:Intracellular cytokine profile of CD14 positive cells in patients with hematologic malignancies and solid tumors during hematologic recovery phase after intensive chemotherapy designed to mobilize peripheral blood stem cells. 1129 19

Two common features in human immunodeficiency virus infection and acquired immunodeficiency syndrome, rheumatoid arthritis, and hematologic malignancies including multiple myeloma are elevated serum levels of beta(2)-microglobulin (beta(2)M) and activation or inhibition of the immune system. We hypothesized that beta(2)M at high concentrations may have a negative impact on the immune system. In this study, we examined the effects of beta(2)M on monocyte-derived dendritic cells (MoDCs). The addition of beta(2)M (more than 10 microg/mL) to the cultures reduced cell yield, inhibited the up-regulation of surface expression of human histocompatibility leukocyte antigen (HLA)-ABC, CD1a, and CD80, diminished their ability to activate T cells, and compromised generation of the type-1 T-cell response induced in allogeneic mixed-lymphocyte reaction. Compared with control MoDCs, beta(2)M-treated cells produced more interleukin-6 (IL-6), IL-8, and IL-10. beta(2)M-treated cells expressed significantly fewer surface CD83, HLA-ABC, costimulatory molecules, and adhesion molecules and were less potent at stimulating allospecific T cells after an additional 48-hour culture in the presence of tumor necrosis factor-alpha and IL-1beta. During cell culture, beta(2)M down-regulated the expression of phosphorylated mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), and mitogen-induced extracellular kinase (MEK), inhibited nuclear factor-kappaB (NF-kappaB), and activated signal transducer and activator of transcription-3 (STAT3) in treated cells, all of which are involved in cell differentiation and proliferation. Thus, our study demonstrates that beta(2)M at high concentrations retards the generation of MoDCs, which may involve down-regulation of major histocompatibility complex class I molecules, inactivation of Raf/MEK/ERK cascade and NF-kappaB, and activation of STAT3, and it merits further study to elucidate the underlying mechanisms.
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PMID:Beta 2-microglobulin as a negative regulator of the immune system: high concentrations of the protein inhibit in vitro generation of functional dendritic cells. 1253 97

Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone marrow stromal cells through an interaction between adhesion molecules present on myeloma plasma cells and their respective receptors that are present on bone marrow stromal cells. In addition, control over production of IL-6 may be exerted by other ILs such as IL-1beta and IL-10. Among target cells, the growth of normal and myeloma plasma cells is supported by IL-6, which also induces the differentiation of myeloma plasmablastic cells into mature plasma cells. This last action also is shared by IL-3, IL-4, and, most likely, IL-8. Evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor (sIL-6R), and soluble IL-2 receptor (sIL-2R), together with the activity exerted by IL-3 and IL-4 on some cellular subsets, may constitute an additional element in the differential diagnosis of borderline cases. However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high beta(2) microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity. Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to beta(2) microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.
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PMID:A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. 1273 43

Angiogenesis plays an important role in solid tumors and hematologic malignancies. The prognostic significance of angiogenic factors in adult acute lymphoblastic leukemia (ALL) remains ambiguous. We therefore analyzed the impact of angiogenic factor levels on overall survival of newly diagnosed adult ALL patients. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-1 receptor alpha (IL-1Ralpha), IL-6, IL-8, VEGF receptors VEGFR1 and VEGFR2, and thrombopoietin (TPO) were measured in plasma samples of 95 patients by enzyme-linked immunosorbent assay (ELISA). In a univariate Cox proportional hazards model, higher levels of IL-1Ralpha, IL-8, VEGFR1, and VEGFR2 were predictive of poor survival. In contrast, higher levels of VEGF were predictive of longer survival, and higher levels of bFGF suggested a similar trend (P = .09). The multivariate model simultaneously included VEGF (relative risk [RR] for death, 8.01; P = .001 for levels less than or equal to 19.5 pg/mL), IL-1Ralpha (RR, 5.12; P = .007 for levels greater than 373 pg/mL), and VEGFR2 (RR, 4.01; P = .04 for levels greater than 8222 pg/mL) as independent factors for survival. Of interest is the association of high levels of VEGF with good prognosis and higher levels of VEGF receptors with poor outcome. These data reflect the complexity by which angiogenic factors may affect the clinical behavior of patients with ALL, and this complexity should be considered in any therapeutic strategy incorporating antiangiogenic agents.
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PMID:Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia. 1612 21

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

The immunomodulatory activities of recombinant human interleukin-11 (rhIL-11) were investigated in a clinical trial among patients with hematological malignancy, randomized to either rhIL-11 or placebo throughout chemotherapy. Daily serum concentrations of sTNFRI, IL-6, IL-8, TNFalpha, and CRP were measured. Higher sTNFRI levels [mean pg/ml (95% CI)] were detected in patients receiving rhIL-11 compared to placebo [1749.7 (1626-1882.9) versus 1038.5 (953.3-1131.3)] respectively (P = 0.01) for all 898 observations and during febrile days [2327.6 (2142.6-2528.2) versus 1308.9 (1163-1473.2), P = 0.12] and during days without infection [1406.6 (1266.1-1563) versus 871.3 (774.9-979.6), P < 0.001]. A similar pattern in CRP concentrations was observed. Multivariate analysis indicated rhIL-11 was associated with elevated sTNFRI or CRP independent of infectious episodes and other factors. 7 patients (all receiving placebo) of 40 had elevated TNFalpha levels. IL-6 and IL-8 levels were not substantially affected by rhIL-11. Bacteremia, fungal infections, and fever of unknown origin (FUO) were reduced in rhIL-11-treated patients. Given the role of sTNFRI in dampening the deleterious effects of a hyperactive TNFalpha environment, rhIL-11-induced upregulation of sTNFRI shedding is a potentially important mechanism for modulating immune and inflammatory responses in humans.
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PMID:Modulation of the systemic inflammatory response by recombinant human interleukin-11: a prospective randomized placebo controlled clinical study in patients with hematological malignancy. 1664 88

Most invasive fungal infections such as candidemia are frequent in patients with hematologic malignancies. We measured cytokines/chemokines (IL-6, IL-8, monocytic chemoattractant protein 1, RANTES and epithelial neutrophil-activating peptide 78), soluble molecules (sFas, sE-selectin and soluble vascular cell adhesion molecule 1) and platelet activation markers (soluble CD40 ligand, sP-selectin and platelet-derived microparticles) in patients with hematologic malignancies under prophylactic treatment with an antifungal drug (fosfluconazole). We classified patients into 2 groups by the level of beta-D-glucan. The level of C-reactive protein was higher in the high beta-D-glucan group (>5 pg/ml) than in the low beta-D-glucan group. However, there were no differences in the levels of other parameters (peripheral blood cells, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, blood urea nitrogen and creatinine). Patients in the high beta-D-glucan group exhibited a significant elevation of several chemokines, soluble molecules and platelet activation markers compared with those in the low beta-D-glucan group, but the levels of IL-8, monocytic chemoattractant protein 1 and sFas did not differ significantly. The levels of C-reactive protein and IL-6 increased significantly after 1 or 2 weeks on fosfluconazole in both groups. In contrast, the high beta-D-glucan group exhibited a significant decrease in chemokines, soluble markers and platelet-derived microparticles compared with the low beta-D-glucan group after treatment with fosfluconazole, although the patients in the low beta-D-glucan group exhibited no significant changes. Furthermore, the levels of RANTES, epithelial neutrophil-activating peptide 78, soluble vascular cell adhesion molecule 1 and sE-selectin correlated positively with platelet-derived microparticles in the high beta-D-glucan group. These findings suggest that fungal infection may modulate the vascular events in which some platelet-related chemokines are involved.
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PMID:Elevation of activated platelet-dependent chemokines and soluble cell adhesion molecules in patients with hematologic malignancies and high levels of beta-D-glucan. 1833 12

Infectious complications in neutropenic patients are a major cause of morbidity and mortality. Clinical signs are unspecific and fever can be attributed to other causes. Inflammatory biomarkers have emerged as potentially useful in diagnosis of bacterial and fungal infection. Levels of several biomarkers were measured in patients with hematological malignancy at diagnosis and at the beginning of neutropenia due to cytostatic treatment or after hematopoietic stem cell transplantation, and daily until 6 days after presenting fever. Procalcitonin (PCT) and neopterin levels were not elevated at diagnosis or at the beginning of neutropenia. C-reactive protein (CRP) was moderately elevated. PCT levels were significantly higher in patients with Gram-negative bacteremia at 24-48 h after the onset of fever. Patients with probable fungal infection presented elevated PCT values when fever persisted for more than 4-5 days. CRP was more sensitive to predict bacteremia (both Gram-positive and Gram-negative) but the specificity was low. Neither neopterin, IL-6 nor IL-8 presented significant differences according to the origin or etiology of fever. Since it showed a high negative predictive value of Gram-negative bacteremia, clinical prediction rules that attempt to predict a high risk of severe infection might be improved by including measurement of PCT.
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PMID:Evaluation of procalcitonin, neopterin, C-reactive protein, IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia. 1866 97


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