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

Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients receiving placebo improved compared with 44% receiving 1 mg/kg cA/2 and 79% receiving 10 mg/kg. Between 2 to 4 repeated cycles of cA2 were administered to 7 patients and all patients showed improvement of a similar magnitude with each cycle. These data support our proposition that TNF alpha is implicated in the pathogenesis of RA, and is thus a key therapeutic target. Monoclonal anti-TNF alpha antibodies control disease flares and are candidate agents for longer-term control of RA, although repeated therapy with cA2 is associated with anti-idiotypic responses in 50% of patients and a trend toward shortening of the duration of response. In the DBA/1 arthritic mice, synergy of action of anti-TNF and anti-CD4 is observed together with suppression of an anti-globulin response, indicating one way in which benefit might be augmented in the future.
 ...
PMID:Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease. 759 Aug 14

Interleukin-8 (IL-8) has been associated with a variety of hyperinflammatory states and adverse clinical events. Circulating IL-8 levels correlate with the severity of tissue trauma, and excessive elevations of IL-8 are associated with postinjury adult respiratory distress syndrome and multiple organ failure. While IL-8 is a potent neutrophil (PMN) chemoattractant and activator and enhances PMN transendothelial migration, it also acts to inhibit PMN adhesion to stimulated endothelial cells (ECs). We hypothesized that IL-8 could interact directly with ECs to increase permeability independent of PMNs. Human umbilical vein ECs (HUVECs) were cultured on collagen-coated micropore filters, and integrity of the EC monolayer measured by albumin flux across the filter. Cytochalasin D was used as a positive control. IL-8 induced increased permeability at a concentration of 1000 ng/mL. This effect was abrogated by preincubation of HUVECs with a protein synthesis inhibitor (cycloheximide). These data suggest a role for IL-8 in promoting endothelial leak independent of PMNs, via a mechanism involving protein synthesis.
 ...
PMID:Interleukin-8 increases endothelial permeability independent of neutrophils. 763 16

Fibrosis of the pulmonary parenchyma is a frequent and serious complication of scleroderma (systemic sclerosis, SSc), resulting in significant morbidity and mortality. During the past decade data have accumulated in support of an inflammatory process affecting the alveoli and distal airways that culminates in irreversible fibrosis in many SSc patients. Recent findings indicate the presence of lung fibroblasts with altered phenotype and biologic activity (myofibroblasts), perhaps arising from the influence of cytokines on resident lung fibroblasts. Acute-phase inflammatory cytokines such as IL-1 alpha, TNF-alpha, MIP-1 alpha, IL-8 and RANTES are increased in SSc bronchoalveolar lavage (BAL) fluid, as is thrombin, a potent mitogen for lung fibroblasts. Chronic-phase inflammatory and fibrogenic cytokines such as PDGF and TGF-beta are also present in increased amounts in SSc BAL fluid. The inciting event(s) and the process(es) leading to the perpetuation of fibrosis in SSc are unknown. Treatment of SSc lung disease has been empiric and generally disappointing, and it is likely that effective treatment awaits a better understanding of the biological events that regulate collagen and other extracellular matrix synthesis.
 ...
PMID:Interstitial lung disease of systemic sclerosis. 765 Apr 24

Among other mediators, platelet-derived serotonin (5-HT) may contribute to thromboembolic complications of atherosclerosis. We determined whether long-term oral treatment with the 5-HT2 antagonist naftidrofuryl (NAF, 50 mg/kg daily for 12 weeks) alters platelet function in cholesterol-fed (1%) rabbits. Hypercholesterolemia resulted in marked platelet hyperreactivity to collagen and ADP. This included increased aggregation, ATP secretion, and thromboxane formation; e.g., collagen-induced (1.2 micrograms/ml) platelet aggregation was stimulated to 210 +/- 10 mm/30 s in cholesterol-fed rabbits as compared with 108 +/- 9 mm/30 s in rabbits fed a standard diet (p < 0.05). Inhibition of ADP-stimulated platelet activation by the prostacyclin mimetic iloprost was significantly reduced. NAF did not reduce plasma cholesterol in hypercholesterolemia, but prevented enhanced platelet aggregation, thromboxane formation, and ATP secretion. NAF treatment significantly reduced collagen-induced (1.2 micrograms/ml) aggregation to 81 +/- 20 mm/30 s in these animals (p < 0.05). NAF also inhibited functional desensitization of platelets to iloprost, but did not alter the impaired binding of [3H]iloprost to platelet membranes in hypercholesterolemic animals. NAF also did not change any of these parameters in normocholesterolemic rabbits. These data suggest beneficial effects of NAF on platelet hyperreactivity in experimental hypercholesterolemia which may also be relevant for its clinical use.
 ...
PMID:Oral naftidrofuryl prevents platelet hyperreactivity ex vivo and inhibits functional desensitization to prostacyclin in hypercholesterolemic rabbits. 767 70

Pulmonary fibrosis corresponds to an accumulation of collagens and other proteins of the extracellular matrix in the interstitium and alveoli. Biochemical and cellular mechanisms of pulmonary fibrogenesis remain poorly understood. The cells of the alveolitis (macrophages, lymphocytes and neutrophils) play a key role in producing the factors which regulate the proliferation, chemotactism and secretory activity of the fibroblasts. Amongst these factors the cytokines (interleukins, interferons and growth factors) play a definite but very complex role. Certain cytokines stimulate in vitro the attraction and activation of cells of the alveolitis, as well as the multiplication, migration and secretory activity of fibroblasts. The following cytokines are involved: tumour necrosis factor alpha: (TNF alpha), interleukin 1 (IL-1), interleukin 6 (IL-6) interleukin 8 (IL-8) transforming growth factor beta (TGF beta), platelet derived growth factor (PDGF), insulin like growth factor 1 (IGF-1), fibronectin, monocyte chemotactic protein 1: (MCP-1). Other cytokines, principally the interferons (of alpha, beta or gamma type: IFN alpha, IFN beta, IFN gamma) inhibit in vitro and in vivo the proliferation and the production of collagen by fibroblasts. During the course of human pulmonary fibrosis or in experimental situations, the majority of the cytokines mentioned above are produced in excess in the lung. Without doubt they play an important role in the pathogenesis of fibrosis, even if it is not yet very well known how they interact and contribute in vitro to the process of fibrogenesis. Certain cytokines potentially regulating in the fibrosis are yet to be identified. In the future the use of cytokines and of their inhibitors will perhaps provide new therapies in pulmonary fibrosis.
 ...
PMID:[Cytokines and pulmonary fibroses]. 768 79

Inflammatory malignant fibrous histiocytomas (IMFH) are rare tumors and are frequently associated with leukocytosis. In rare cases, leukemoid reactions were attributed to tumor production of unidentified hematopoietic factors. In this study, we used immunohistochemical techniques to show cytokine immunoreactivity in the malignant cells of two cases of IMFH presenting with leukemoid reactions and compared them with two malignant fibrous histocytomas, noninflammatory type. All four tumors stained positively for stem cell factor (SCF), granulocyte colony-stimulating factor (G-CSF), interleukin-2 (IL-2), IL-4, IL-5, interferon-alpha (IFN-alpha), and insulin-like growth factor-I. Other cytokines detected only in the two IMFH included IL-6, IL-7, IL-8, IFN-gamma, and keratinocyte growth factor. Granulocyte-macrophage-CSF, IL-3, and transforming growth factor-beta staining was present in one of the two IMFH tumors and was not present in the noninflammatory tumors. The immunohistochemical staining was localized to the malignant cells, suggesting deregulated cytokine expression consistent with their monocytic/histocytic origin. Expression of certain cytokines in the IMFH may account for the local inflammatory infiltrate, tumor fibrosis, and the aggressive nature of the malignant cells. We also detected elevated serum levels of SCF, G-CSF, IL-6, and tumor necrosis factor in one or both of the IMFH patients. These latter observations may explain the bone marrow hypercellularity and other paraneoplastic symptoms, including fever, malaise, and weight loss, observed in both patients. Different cytokines present in the two IMFH tumors appear to be responsible for the eosinophilic leukemoid reaction observed in one case and for the granulocytic leukemoid reaction observed in the other patient. They may also be responsible for expansion of the tumor-cell population, fibroblast proliferation, and enhanced secretion of extracellular collagen.
 ...
PMID:Cytokines in inflammatory malignant fibrous histiocytoma presenting with leukemoid reaction. 769 Dec 45

We have examined the capacity of four different chemoattractants/cytokines to promote directed migration of polymorphonuclear leukocytes (PMN) through three-dimensional gels composed of extracellular matrix proteins. About 20% of PMN migrated through fibrin gels and plasma clots in response to a gradient of interleukin 8 (IL-8) or leukotriene B4 (LTB4). In contrast, < 0.3% of PMN migrated through fibrin gels in response to a gradient of tumor necrosis factor alpha (TNF) or formyl-methionyl-leucyl-phenylalanine (FMLP). All four chemoattractants stimulated PMN to migrate through gels composed of collagen IV or of basement membrane proteins (Matrigel), or through filters to which fibronectin or fibrinogen had been adsorbed. PMN stimulated with TNF or FMLP adhered and formed zones of close apposition to fibrin, as measured by the exclusion of a 10-kD rhodamine-polyethylene glycol probe from the contact zones between PMN and the underlying fibrin gel. By this measure, IL-8- or LTB4-treated PMN adhered loosely to fibrin, since 10 kD rhodamine-polyethylene glycol permeated into the contact zones between these cells and the underlying fibrin gel. PMN stimulated with FMLP and IL-8, or FMLP and LTB4, exhibited very little migration through fibrin gels, and three times as many of these cells excluded 10 kD rhodamine-polyethylene glycol from their zones of contact with fibrin as PMN stimulated with IL-8 or LTB4 alone. These results show that PMN chemotaxis is regulated by both the nature of the chemoattractant and the composition of the extracellular matrix; they suggest that certain combinations of chemoattractants and matrix proteins may limit leukocyte movements and promote their localization in specific tissues in vivo.
 ...
PMID:Fibrin regulates neutrophil migration in response to interleukin 8, leukotriene B4, tumor necrosis factor, and formyl-methionyl-leucyl-phenylalanine. 772 53

Our pre-clinical studies have demonstrated a pathogenic role for TNF alpha in RA. Firstly, TNF alpha and its receptors are upregulated and co-expressed in the synovium and cartilage-pannus junction of RA joints. Secondly, mononuclear cells from RA joints maintained in culture produce many cytokines with pro-inflammatory activity, including TNF alpha. Neutralizing TNF alpha antibodies in vitro reduces the production of these pro-inflammatory cytokines, including IL-1, IL-8, and GM-CSF. Thirdly, when injected into arthritic DBA/l mice with collagen-induced arthritis, monoclonal anti-TNF antibodies decrease inflammatory damage of joints. Clinical trials employing cA2, a monoclonal chimeric anti-TNF alpha antibody, in open-label and randomized placebo-controlled studies have demonstrated a dose-dependent efficacy with impressive improvement in disease activity and acute phase responses lasting several weeks. We conclude that TNF alpha is a critical mediator of inflammation in RA and is an important therapeutic target in this disease.
 ...
PMID:Targeting TNF alpha for the therapy of rheumatoid arthritis. 776 56

Two human skin recombinants, the epidermis reconstructed on the deepidermized dermis (RE-DED) or on fibroblast-populated collagen matrix (Living Skin Equivalent, LSE), were used to study the irritating effect of sodium lauryl sulfate (SLS). The extent of cytotoxicity induced after a 24-hour exposure period to increasing concentrations of SLS (0-5%) was evaluated on the basis of (1) morphological perturbations, (2) changes in the expression of differentiation-specific protein markers (keratin 1, 10, 6, 16, involucrin and transglutaminase), (3) cell membrane integrity (LDH leakage) and (4) release of proinflammatory mediators (PGE2, IL-1, IL-6 and IL-8). SLS induced significant changes in epidermal morphology and changes in the expression and localization of differentiation-specific protein markers when applied topically in concentrations higher than 1% on RE-DED and higher than 0.1% on LSE. The exposure of both human skin recombinants to SLS resulted in a dose-dependent release of LDH, PGE2 and IL-1 alpha and in an increase in keratinocyte intracellular IL-1 levels. Upon application of 5% SLS on RE-DED the total (intra- and extracellular) IL-1 levels remained high but due to cell damage the intracellular IL-1 level was markedly decreased and the extracellular IL-1 level increased. Similar observations have been made with LSE after application of 0.5% SLS. However, with LSE the extracellular IL-1 alpha levels were found to be about 100 times lower than those measured with RE-DED. Exposure of LSE to SLS induced a marked increase of IL-6 production in fibroblasts incorporated in the collagen matrix. Contrary to LSE, both intra- and extracellular levels of IL-6 were low in unexposed controls and were only marginally modulated by the exposure of the RE-DED to SLS. In addition, a dose-dependent increase in IL-8 release was observed upon application of SLS on RE-DED. The results of the present study indicate that concentrations of SLS required to induce epidermal irritancy in vitro approximate those inducing irritation in human skin in vivo. All parameters used in the present study for evaluation of toxicity can serve as useful endpoints for screening of contact skin irritancy in vitro. Compared to RE-DED, the LSE seems to be more susceptible to SLS. The differences in sensitivity between LSE and RE-DEd can be ascribed to reported differences in their stratum corneum barrier function.
 ...
PMID:Use of human skin recombinants as an in vitro model for testing the irritation potential of cutaneous irritants. 778 25

Bestatin is an immunomodulatory peptide that stimulates the humoral and cell-mediated immune system. It also has an inhibitory effect on multiple aminopeptidases. Recently we found that aminopeptidase N inactivates interleukin-8 in vitro. Bestatin successfully suppresses the effect of aminopeptidase N on interleukin-8. During cervical maturation many biochemical changes occur including decrease in collagen concentration and increase in collagenase and elastase activities. Interleukin-8, which has a potent neutrophil chemotactic effect, was found to induce cervical ripening in rabbits. The combination of interleukin-8 with bestatin also induced cervical ripening by providing approximately regular levels of neutrophil numbers, collagenase, and elastase activities. We therefore suggest that this regulatory mechanism also takes place in vivo through the inhibitory effect of bestatin on aminopeptidase N.
 ...
PMID:Regulatory effect of aminopeptidase inhibitor (bestatin) on the cervix during induction of ripening by interleukin-8. 779 Jul 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>