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)

We investigated cellular responses in a rabbit to i.v. administration of five established chemotactic factors (leukotriene B4 (LTB4), platelet-activating factor (PAF), C5a, N-Formyl-Met-Leu-Phe (F-MLF), and IL-8), and each exerted a characteristic effect on circulating white blood cell levels. All five factors induced a rapid and transient leukopenia. The blood was nearly devoid of circulating neutrophils 5 min after administration of each chemotactic factor. Other leukocytes were also variably depleted during the leukopenic phase, including eosinophils, basophils, monocytes, and lymphocytes. The lymphocyte numbers remained significantly depressed (approximately 30%) for as long as 3 h after administration of PAF or f-MLF. Each chemotactic factor produced a marked neutrophilia (i.e., 250-400% of baseline levels) after the initial leukopenia. Eosinophil numbers were elevated along with the neutrophil response in the C5a- and LTB4-treated animals. Basophil levels were significantly elevated only in LTB4-treated animals. The cellular response to PAF, f-MLF, and IL-8 appeared to be specific for the neutrophils. The kinetic profiles of the neutrophilia induced by PAF (10 micrograms/kg) or f-MLF (2.5 micrograms/kg) were similar, with maximal responses occurring 3 to 4 h after administration. In contrast, LTB4 (10 micrograms/kg), IL-8 (2.5 micrograms/kg), and C5a (5 micrograms/kg) induced a more rapid neutrophilia, with peak responses occurring 1 to 1.5 h after injection, and remaining elevated for 3 to 4 h. In all animals the neutrophilia was accompanied by a relative increase in the number of nonsegmented neutrophils (bands), suggesting that a major component of leukocytosis is caused by the release of bone marrow reserves. Phenidone (10 mg/kg), a dual cyclooxygenase/5-lipoxygenase inhibitor, affected neither the neutropenia nor the neutrophilia induced by C5a, f-MLF, or PAF. The protein synthesis inhibitor actinomycin D also failed to suppress neutrophil responses induced by either C5a or PAF. These results suggest that leukocytosis is a common response induced by all neutrophil chemotactic factors. Leukocytosis appears to be a direct result of the dynamic adaptive response of neutrophils to chemotactic factor stimulation without involvement of a secondary mediator system.
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PMID:Neutrophil chemotactic factors promote leukocytosis. A common mechanism for cellular recruitment from bone marrow. 131 Jul 8

2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificity for the c-erbB-2 and Fc gamma RIII extracellular domains. This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-erbB-2 gene product of the HER2/neu proto-oncogene by human natural killer cells and mononuclear phagocytes expressing the Fc gamma RIII A isoform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-overexpressing tumors were treated with 1 h i.v. infusions of 2B1 on days 1, 4, 5, 6, 7, and 8 of a single course of treatment. Three patients were treated with daily doses of 1.0 mg/m2, while six patients each were treated with 2.5 mg/m2 and 5.0 mg/m2, respectively. The principal non-dose-limiting transient toxicities were fevers, rigors, nausea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at the 5.0 mg/m2 dose level in two patients who had received extensive prior myelosuppressive chemotherapy. Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding properties were retained. The pharmacokinetics of this murine antibody were variable and best described by nonlinear kinetics with an average t 1/2 of 20 h. Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma. Brisk human anti-mouse antibody responses were induced in 14 of 15 patients. Several minor clinical responses were observed, with reductions in the thickness of chest wall disease in one patient with disseminated breast cancer. Resolution of pleural effusions and ascites, respectively, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon cancer. Treatment with 2B1 BsMAb has potent immunological consequences. The maximum tolerated dose and Phase II daily dose for patients with extensive prior myelosuppressive chemotherapy was 2.5 mg/m2. Continued dose escalation is required to identify the maximally tolerated dose for patients who have been less heavily pretreated.
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PMID:Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 755 34

Septic shock following gram-negative infection is a leading cause of mortality in critically ill patients, accounting for nearly 200,000 deaths a year. The exaggerated production of tumor necrosis factor-alpha (TNF alpha) is known to contribute to hemodynamic collapse and the hematological dyscrasia associated with gram-negative sepsis. Although previous studies have shown TNF alpha antibodies and TNF immunoadhesins to be effective in experimental gram-negative sepsis, we postulated that administration of a novel construct of two modified soluble p55 receptors linked to polyethylene glycol (PEG-BP-30) would also attenuate the hemodynamic and hematologic alterations to lethal Escherichia coli septic shock in non-human primates. Nine adult female and male baboons (Papio anubis), weighing 10-17 kg, were anesthetized and invasively monitored. The nine animals were randomized to receive either 0.2 mg/kg body wt PEG-BP-30 (n = 3), 5.0 mg/kg body wt PEG-BP-30 (n = 3), or placebo (n = 3). One hour after pretreatment, animals were infused with 5-10 x 10(10) CFU/kg of live E. coli iv and vital signs were recorded for the next 8 hr. Arterial blood was drawn for baseline parameters and throughout the study to obtain total and differential white blood cell and platelet counts and cytokine levels (TNF alpha, IL-1 beta, IL-6, IL-8). E. coli bacteremic baboons receiving only placebo demonstrated a significant fall in mean blood pressure and leukopenia. Two of the three animals expired. In contrast, five of the six baboons receiving the PEG-BP-30 survived and these animals exhibited markedly attenuated declines in blood pressure and leukocyte numbers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:PEG-BP-30 monotherapy attenuates the cytokine-mediated inflammatory cascade in baboon Escherichia coli septic shock. 763 Jan 20

To investigate the effects of a recombinant endotoxin-binding protein, bactericidal/permeability-increasing protein (rBPI23), on cytokine release and neutrophil activation in endotoxemia in humans, 8 volunteers were challenged twice with endotoxin and concurrently received either rBPI23 or placebo in a randomized, placebo controlled, double-blind crossover study, rBPI23 treatment significantly lowered circulating endotoxin levels (P = .02) and resulted in a significant reduction in the release of tumor necrosis factor (TNF), soluble TNF receptors p55 and p75, interleukin (IL)-6, IL-8 (P < .01 for each), and IL-10 levels (P = .02) but did not prevent the endotoxin-induced rise in body temperature. The early endotoxin-induced leukopenia was blunted (P = .08), and neutrophil degranulation, as measured by circulating levels of elastase/alpha 1-antitrypsin complexes (P = .03) and lactoferrin (P < .01), was largely prevented by rBPI23. The results of this study indicate that rBPI23 is capable of neutralizing many of the biologic effects of endotoxin in humans.
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PMID:Inhibition of endotoxin-induced cytokine release and neutrophil activation in humans by use of recombinant bactericidal/permeability-increasing protein. 779 4

1. To assess in vivo chemotactic activity of tumour necrosis factor (TNF), interleukin-1 (IL-1), IL-8, and cytokine-induced neutrophil chemoattractant (CINC), we injected these cytokines into the pleural cavity of rats. 2. CINC (0.1-1 microgram) and recombinant human IL-8 (rhIL-8, 0.2-5 micrograms) caused neutrophil infiltration into the rat pleural cavity in a dose-dependent fashion, peaking at 3 h. The number of leukocytes in the peripheral blood did not change significantly. 3. RhTNF alpha and rhIL-1 alpha also induced neutrophil accumulation. The dose response curves of rhTNF alpha (0.67 ng-6.7 micrograms) and rhIL-1 alpha (0.45 ng-4.5 micrograms) at 3 h were bell shaped. On the other hand, unlike CINC and rhIL-8, rhTNF alpha and rhIL-1 alpha caused transient marked leukopenia at 3 h in a simple dose-dependent fashion. 4. Concomitant injection of actinomycin D dose-dependently and completely at 10 micrograms inhibited neutrophil infiltration induced by rhTNF alpha (0.67 microgram) and rhIL-1 alpha (0.45 microgram) at 3 h. However, that induced by CINC or rhIL-8 was not affected by actinomycin D. 5. Peaking at 1 h, CINC production in the pleural cavity was found after intrapleural injection of rhTNF alpha (0.67 microgram) or rhIL-1 alpha (0.45 microgram), but not after that of rhIL-8 (5 micrograms). The CINC production induced by rhTNF alpha or rhIL-1 alpha and the neutrophil infiltration was suppressed by concomitant injection of actinomycin D (1 and 10 micrograms). 6. These results indicate that CINC and IL-8 themselves are direct chemoattractants for neutrophils, whereas TNF and IL-1 induce neutrophil infiltration indirectly via newly synthesized mRNA for chemotactic protein including CINC, which may be involved in neutrophil emigration at local inflammatory sites in rats.
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PMID:Infiltration of neutrophils by intrapleural injection of tumour necrosis factor, interleukin-1, and interleukin-8 in rats, and its modification by actinomycin D. 864 4

The pathogenesis of organ injury induced by extracorporeal circulation involves many inflammatory cascades and cellular components of the immune system. One therapeutic approach is to target the neutrophil and minimize the deleterious effects of neutrophil activation during bypass. Mechanical removal of circulating neutrophils from the perfusate by filtration produced profound leukopenia in a dog model that persisted for 8-12 h post-bypass. The leukocyte-depleted animals had less lung sequestration of white cells than control animals and less evidence of white-cell activation. These differences resulted in significantly improved pulmonary gas exchange in the post-bypass period. Another approach to reducing cardiopulmonary bypass (CPB) neutrophil-mediated injury is modulation of neutrophil-endothelial adherence. One strategy is to improve the biocompatibility of the bypass circuit. Our laboratory measured the upregulation of the neutrophil-adhesion molecules CD11b and CD18 during CPB but did not demonstrate significant differences between membrane and bubble oxygenators. However, studies in pigs undergoing CPB with a standard extracorporeal circuit or a heparin-coated CPB circuit found less pulmonary injury in the heparin-coated group of animals. Specific therapy to inhibit adhesion molecule expression using the anti-inflammatory compound NPC 15669 has shown promise. Marked inhibition of neutrophil CD18 expression during and post-bypass, better gas exchange, and lower pulmonary vascular resistance occurred in the treated animals. The role of cytokines in relation to the morbidity associated with bypass is not clearly defined. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, and IL-8 are usually (but not uniformly) elevated after cardiac operations.
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PMID:Initiation of white cell activation during cardiopulmonary bypass: cytokines and receptors. 893 77

Cancer patients who are leukopenic due to chemotherapy are susceptible to bacterial infections. Normally, clinical conditions during bacterial infections are caused by pathogen-associated molecular patterns, which are components that bind to Toll-like receptor (TLR) 2 (TLR-2) and TLR-4 on leukocytes, resulting in the production of inflammatory cytokines. The mechanism of this inflammatory response in cancer patients with diminished numbers of leukocytes is not completely clear. The levels of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha measured in the circulation of leukopenic cancer patients are lower than those measured in that of nonleukopenic patients during bacterial infections, whereas plasma interleukin 8 (IL-8) levels show distinct identical increases during bacterial infections in both leukopenic and nonleukopenic patients. Normally, these cytokines are mainly secreted by leukocytes. In cancer patients with bacterial infections and a diminished number of leukocytes, other sources of IL-8 production, such as endothelial cells, might be expected. Endothelial cells instead of leukocytes become the most important producers of IL-8 during bacterial infections in patients with chemotherapy-induced leukopenia through TLR-2 and TLR-4 signaling. Whole blood samples from six cancer patients were stimulated with lipopolysaccharide (LPS), and then IL-8 concentrations in supernatants were measured. Further, human umbilical vein endothelial cells (HUVECs) were incubated with sera from leukopenic cancer patients with or without bacterial infections, and then IL-8 concentrations in supernatants were measured (n = 6). In addition, the same HUVEC experiment was performed with the addition of neutralizing antibodies against TLR-2 and TLR-4. During leukopenia (<10(9) cells/liter), LPS stimulation of whole blood did not result in an increase in IL-8 levels. However, when endothelial cells were incubated with sera from leukopenic cancer patients during bacterial infections, a three- to eightfold increase in IL-8 production was found, compared to the IL-8 production found after incubation with sera from patients without signs of infections. This increase did not reflect a higher level of IL-8 already present in the sera. Further, we demonstrated that IL-8 production induced in endothelial cells by sera from patients with documented gram-negative infections could be reduced significantly by up to 40% when the cells were incubated with neutralizing antibodies against TLR-4 (P = 0.028). The addition of TLR-2 antibodies slightly enhanced the reduction of IL-8 production. These results suggest that during bacterial infections in cancer patients with markedly diminished numbers of leukocytes, endothelial cells become important producers of IL-8 through TLR-4 signaling and, to a lesser extent, TLR-2 signaling.
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PMID:Endothelial cells are main producers of interleukin 8 through Toll-like receptor 2 and 4 signaling during bacterial infection in leukopenic cancer patients. 1285 86

Leukocytopenia can be caused by depressed production, increased peripheral destruction, or excessive peripheral pooling. Leukocyte margination is one of the mechanisms responsible for excessive peripheral pooling. A reversible leukocyte margination is caused by an increase in pro-inflammatory cytokines. However, there are limited data for this phenomenon in clinical conditions. We describe a case of unexpected transient leukocytopenia after exchanging an extracorporeal membrane oxygenation (ECMO) system used to treat severe cardiogenic pulmonary edema. To assess the cause of the leukocytopenia, the serum concentrations of pro-inflammatory cytokines and selectins were measured. The concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were markedly, but transiently, elevated in relation to the leukocytopenia. The transient leukocytopenia with pulmonary margination appeared to be caused by a steep surge of pro-inflammatory cytokines stimulated by hypoxia/reoxygenation during the exchange of the ECMO system. This case may suggest the mechanisms responsible for leukocytopenia in the clinical entity referred to as "systemic inflammatory response syndrome"
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PMID:Transient leukocytopenia associated with a steep surge of pro-inflammatory cytokines in a patient with severe cardiogenic pulmonary edema. 1710 60

Measles virus (MV) induces profound suppression of the immune response during and for weeks after acute infection. On the other hand, virus-specific immune responses that mediate viral clearance and confer long-lasting immunity are efficiently generated. To investigate this paradox, we studied the immune responses to MV using a monkey model of acute measles. Cynomolgus monkeys were experimentally infected with wild-type MV (MV-HL) and showed marked leukopenia associated with a steady reduction in CD4+ T cell numbers for 18 days post-inoculation. Transient expression of interferon and IL-6 were observed in the serum between 4 and 6 days post-inoculation, and IL-10 levels increased after 11 days post-inoculation. Interestingly, IL-8 showed a three-peak increase that correlated with an increase in neutrophils. A non-human primate model of measles allows the early immune response against MV to be studied in more detail.
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PMID:Immune responses against measles virus in cynomolgus monkeys. 1751 93

The liver and lung are not only described as "target organs" in sepsis in most species, but are purported to be sources of circulating inflammatory mediators central to the systemic inflammatory response syndrome (SIRS). As we have recently reported an inflammatory response in the laminar tissue in laminitis similar to that described in "target organs" in human sepsis, we investigated the inflammatory response of the lung and liver in the black walnut extract (BWE) model of equine laminitis to determine (1) if a similar systemic inflammatory response occurs in this laminitis model as described for these organs in human sepsis, and (2) if these organs may be an important source of the inflammatory mediators leading to laminar inflammation. Real-time quantitative PCR (RT-qPCR) was used to measure hepatic and pulmonary mRNA concentrations of IL-1beta, IL-4, IL-6, IL-8, IL-10, TNF-alpha, COX-1 and COX-2. Hepatic samples were assessed from two time points in the developmental/prodromal period: (1) 1.5h post-BWE administration (BWE-1.5H, n = 5), and (2) the "developmental time point" (onset of leukopenia, approximately 3h post-BWE administration, BWE-DEV, n = 5). Pulmonary samples were only assessed for the BWE-DEV group. One control group (CON-3H, n = 5) was used for both the 1.5H and DEV groups. Finally, CD13 immunohistochemistry was performed to assess leukocyte emigration into hepatic and pulmonary parenchyma. Hepatic and pulmonary mRNA concentrations of the proinflammatory cytokines IL-6, IL-8 and TNF-alpha were significantly increased (P < 0.05) in BWE-1.5H and BWE-DEV groups compared to the control group; IL-1beta mRNA concentrations were only increased in the lung. The "anti-inflammatory" cytokines, IL-10 and IL-4, underwent transient decreases at different time points. Significant increases in parenchymal leukocyte numbers occurred in both the lung and liver at the BWE-DEV time point. Hepatic and pulmonary proinflammatory cytokine expression differ from that previously reported for the laminae in that TNF-alpha was increased in the hepatic and pulmonary tissues, the increases in expression of IL-6 and IL-8 are dramatically smaller for the liver and lung compared to those reported for the laminae, and the peak changes appear to occur later in the disease process in the liver than in the laminae (BWE-DEV in liver vs. 1.5H in the laminae).
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PMID:Indices of inflammation in the lung and liver in the early stages of the black walnut extract model of equine laminitis. 1912 60


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