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)

Defensins, a family of small, cationic, antimicrobial peptides, are found in mammals, insects and plants. alpha-defensins are stored in granules of neutrophils and released upon activation by exocytosis. It was shown here that human neutrophil peptide (HNP), at concentrations of 10(-8) -10(-9) M, up-regulated the expression of TNF-alpha and IL-1 beta in monocytes activated with Staphylococcus aureus or PMA, while expression of IL-10 mRNA was down-regulated and production of IL-8 was not affected. HNP alone was unable to induce TNF-alpha or IL-1 beta expression in resting monocytes. At concentrations of 10(-4) -10(-5)M, HNP was cytotoxic for monocytes in serum-free medium. The cytotoxicity was abrogated in the presence of serum, while a cytokine-modulating effect of HNP was observed in the presence of serum and in whole blood, suggesting that this mechanism may function in vivo. Similarly, serum did not abrogate bactericidal activity of HNP. It was also demonstrated herein that HNP at 10 (-8) -10(-9) M, attenuated the inhibitory action of dexamethasone on TNF-alpha production. In parallel to monocyte studies, we have showed that HNP at concentrations ranging from 10(-9)M to 10(-6)M caused about 5-fold suppression of VCAM-1 expression in TNF-alpha-activated human umbilical vein endothelial cells, while the ICAM-1 expression was not affected. Our findings suggest that neutrophil defensins have the potential to modulate the inflammatory responses through regulation of cytokine production and adhesion molecule expression.
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PMID:Neutrophil alpha-defensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. 1090 5

Cytokines produced by activated macrophages and Th2 cells within the lung play a key role in asthma-associated airway inflammation. Additionally, recent studies suggest that the molecule CD40 modulates lung immune responses. Because airway epithelial cells can act as immune effector cells through the expression of inflammatory mediators, the epithelium is now considered important in the generation of asthma-associated inflammation. Therefore, the goal of the present study was to examine the effects of proinflammatory and Th2-derived cytokines on the function of CD40 in airway epithelia. The results show that airway epithelial cells express CD40 and that engagement of epithelial CD40 induces a significant increase in expression of the chemokines RANTES, monocyte chemoattractant protein (MCP-1), and IL-8 and the adhesion molecule ICAM-1. Cross-linking epithelial CD40 had no effect on expression of the adhesion molecule VCAM-1. The proinflammatory cytokines TNF-alpha and IL-1beta and the Th2-derived cytokines IL-4 and IL-13 modulated the positive effects of CD40 engagement on inflammatory mediator expression in airway epithelial cells. Importantly, CD40 ligation enhanced the sensitivity of airway epithelial cells to the effects of TNF-alpha and/or IL-1beta on expression of RANTES, MCP-1, IL-8, and VCAM-1. In contrast, neither IL-4 nor IL-13 modified the effects of CD40 engagement on the expression of RANTES, MCP-1, IL-8, or VCAM-1; however, both IL-4 and IL-13 attenuated the effects of CD40 cross-linking on ICAM-1 expression. Together, these findings suggest that interactions between CD40-responsive airway epithelial cells and CD40 ligand+ leukocytes, such as activated T cells, eosinophils, and mast cells, modulate asthma-associated airway inflammation.
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PMID:Proinflammatory and Th2-derived cytokines modulate CD40-mediated expression of inflammatory mediators in airway epithelia: implications for the role of epithelial CD40 in airway inflammation. 1092 9

The expression of adhesion molecules on vascular endothelial cells determines the pattern of migration and extravasation of leucocytes in inflammation and immunity. Here we show that costimulation with CD40 ligand (CD40L) and interleukin (IL)-4 (or IL-13) gives rise to a unique pattern of adhesion molecule expression by human umbilical vein endothelial cells (HUVEC). CD40 ligation alone enhanced expression of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin whereas IL-4 and IL-13 increased expression of VCAM-1 and P-selectin but not ICAM-1 or E-selectin. When IL-4 and CD40L were combined there was an additional increase of both VCAM-1 and P-selectin, but ICAM-1 and E-selectin were both inhibited. The combined effects of IL-4 and CD40L signalling were not the result of altered response kinetics, enhanced sensitivity of the endothelium, or increased expression of CD40 or the IL-4 receptor. The rise in VCAM-1 expression induced by combined IL-4 and CD40L stimulation was slower and more sustained than with tumour necrosis factor-alpha (TNF-alpha) and occurred only on a subset (75-80%) of the endothelial cell population compared to 100% with TNF-alpha. Costimulation with IL-4 and CD40L increased adhesion of T cells and B cells above levels obtained with either signal alone, but decreased adhesion of neutrophils. Furthermore, CD40 and IL-4 synergistically increased IL-6 but decreased IL-8 production by HUVEC. These results show that interactions between IL-4 and CD40 on endothelial cells give rise to specific patterns of adhesion molecule expression and cytokine production that may have important implications for lymphocyte and neutrophil migration and function at sites of inflammation.
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PMID:Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin-4 selectively induces expression of vascular cell adhesion molecule-1 and P-selectin resulting in preferential adhesion of lymphocytes. 1092 70

To examine neutrophil transepithelial migration in the basolateral-to-luminal direction, bronchial epithelial cells (16HBE) were grown at an air-medium interface on the lower face of permeable supports, and resistance across each membrane was recorded before measuring neutrophil transmigration over 2 h. Subconfluent monolayers (resistance < 250 Omega) permitted high spontaneous migration of neutrophils (7.4+/-1%), which was further enhanced (29.7+/-3%) in response to interleukin (IL)-8 (100 ng/ml). Confluent monolayers (250 to 700 Omega) showed low spontaneous migration (2+/- 0.5%) but responded markedly to IL-8 (12.4+/-1.3%). Left in culture, 16HBE resistances continued to increase and were associated with minimal spontaneous migration (< 0.5%) or responses to IL-8. Using cells in the 250 to 700 Omega range, neutrophil migration to IL-8 was dose-dependent and was enhanced when epithelial cells were incubated with a combination of tumor necrosis factor-alpha and interferon-gamma. Neutrophil migration was stimulus-specific and was reduced by preincubation of epithelial cells with a F(ab')(2) anti-intercellular adhesion molecule (ICAM)-1, or by preincubation of neutrophils with anti-CD18, anti-CD11a, anti-CD11b, or anti-CD11c, but not by anti-CD11d, indicating a role for beta(2)-integrin-ICAM-1 interaction in the migration process.
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PMID:Neutrophil transmigration across human airway epithelial monolayers: mechanisms and dependence on electrical resistance. 1097 Aug 31

Amphotericin B is known to elicit immunomodulatory effects on neutrophil, monocyte, and lymphocyte function. It also has been shown to induce the release of proinflammatory cytokines from human monocytes and macrophages. Release of these cytokines has been associated with the infusion-related toxicity observed after administration of this drug. The present study demonstrates that amphotericin B increases mRNA for the chemokines interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1beta, as well as the cell adhesion molecules intercellular adhesion molecule (ICAM)-1 and CD44 in the human monocytic cell line THP-1. Amphotericin B increased the concentrations of IL-8, MCP-1, and MIP-1beta in a dose-dependent fashion. Amphotericin B also induced expression of ICAM-1 but not CD44 in these cells. Production of these proteins in response to amphotericin B may play a role in the immunomodulatory activity and toxicity of this antifungal agent.
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PMID:Amphotericin B induces expression of genes encoding chemokines and cell adhesion molecules in the human monocytic cell line THP-1. 1097 35

The activation of primary human airway epithelial cells (HAECs) and of the bronchial epithelial cell line BEAS-2B by Chlamydia pneumoniae, an important respiratory pathogen, was characterized. A time-dependent enhanced release of interleukin (IL)-8 and prostaglandin-E(2) and an increased expression of the epithelial adhesion molecule intercellular adhesion molecule-1 (ICAM-1), followed by subsequent transepithelial migration of polymorphonuclear neutrophils (PMN), were also demonstrated. The transepithelial PMN migration could be blocked by an anti-ICAM-1 monoclonal antibody (MAb) but not by MAbs against IL-8. In addition, there was an enhanced C. pneumoniae-mediated activation of NF-kappaB within 30-60 min in HAECs and BEAS-2B, which was followed by increases in mRNA synthesis of IL-8, ICAM-1, and cyclooxygenase-2, with maximal effects occurring 2 h after infection. Thus, C. pneumoniae infects and activates HAECs and BEAS-2B and therefore may be able to trigger a cascade of pro- and anti-inflammatory reactions during chlamydial infections.
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PMID:Infection and activation of airway epithelial cells by Chlamydia pneumoniae. 1106 40

IkappaB kinase-1 and IkappaB kinase-2 (IKK1 and IKK2; also called IKKalpha and IKKbeta, respectively) are part of the signal complex that regulates NF-kappaB activity in many cell types, including fibroblast-like synoviocytes (FLS). We determined which of these two kinases is responsible for cytokine-induced NF-kappaB activation in synoviocytes and assessed the functional consequences of IKK1 or IKK2 overexpression and inhibition. FLS were infected with adenovirus constructs encoding either wild-type (wt) IKK1 or IKK2, the dominant negative (dn) mutant of both kinases, or a control construct encoding green fluorescence protein. Analysis of the NF-kappaB pathway revealed that cytokine-induced IKK activation, IkappaB degradation, and NF-kappaB activation was prevented in cells expressing the IKK2 dn mutant, whereas baseline NF-kappaB activity was increased by IKK2 wt. In addition, synthesis of IL-6 and IL-8, as well as expression of ICAM-1 and collagenase, was only increased by IKK2 wt, and their cytokine-induced production was abrogated by IKK2 dn mutant. However, the IKK1 dn mutant did not inhibit cytokine-mediated activation of NF-kappaB or any of the functional assays. These data indicate that IKK2 is the key convergence pathway for cytokine-induced NF-kappaB activation. Furthermore, IKK2 regulates adhesion molecule, matrix metalloproteinase, and cytokine production in FLS.
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PMID:NF-kappa B regulation by I kappa B kinase-2 in rheumatoid arthritis synoviocytes. 1116 Mar 35

Hypoxia is an important factor in the pathophysiology of vascular and inflammatory diseases. Leucocyte infiltration, as a consequence of adhesion molecule up-regulation and chemokine release, is a prominent feature of these diseases. The objective of our study was to investigate the potential role of resident fibroblasts in hypoxia-induced chemotactic responses. We show that MCP-1 and IL-8 mRNA are specifically induced by hypoxia in dermal fibroblasts. This response is paralleled by increased NF-kappaB p65/p50 binding activity, and it is inhibited by pretreatment with N-acetyl-L-cysteine. MCP-1 secreted by fibroblasts is chemotactic for monocytic cells and this activity is significantly increased by hypoxia. Chemotactic index correlates with MCP-1 protein levels and is significantly decreased by neutralizing anti-MCP-1 MoAb. These findings demonstrate the ability of resident fibroblasts to mediate chemotaxis of leucocytes through the release of chemokines in response to hypoxia. Our data point to MCP-1 as an important component in this response, and therefore it may be a potential target in inflammatory responses associated with hypoxia.
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PMID:Hypoxia induces expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8 in human dermal fibroblasts. 1116 95

Macrolides have been used for decades as an important chemotherapeutic agent in the treatment of infectious diseases. In the last 10 years there has also been increasing interest in the interaction between macrolide antibiotics and the immune system. The aim of this review is to focus on the anti-inflammatory action of erythromycin and its derivatives in the treatment of chronic sinusitis and nasal polyps. Systematic clinical investigations have been few and to the author's knowledge there have been no placebo-controlled studies. However there have been, especially from Japan, a number of clinical reports stating that long-term, low-dose macrolide antibiotics are effective in treating chronic sinusitis incurable by surgery or glucocorticosteroid treatment, with an improvement in symptoms varying between 60% and 80% in different studies. In animal studies macrolides have increased mucociliary transport, reduced goblet cell secretion and accelerated apoptosis of neutrophils, all factors that may reduce the symptoms of chronic inflammation. There is also increasing evidence in vitro of the anti-inflammatory effects of macrolides. Several studies have shown macrolides to inhibit interleukin gene expression for IL-6 and IL-8 and also to inhibit the expression of intercellular adhesion molecule essential for the recruitment of inflammatory cells. There is also evidence in vitro, as well as clinical experience, showing that macrolides reduce the virulence and tissue damage caused by chronic bacterial colonization without eradicating the bacteria. The benefit of long-term, low-dose macrolide treatment seems to be that it is, in selected cases, effective when steroids fail. The exact mechanism of action is not known, but it probably involves downregulation of the local host immune response as well as a downgrading of the virulence of the colonizing bacteria. In the future, placebo-controlled studies should be performed to establish the efficacy of macrolides if this treatment is to be accepted as evidence-based medicine.
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PMID:The anti-inflammatory effect of erythromycin and its derivatives, with special reference to nasal polyposis and chronic sinusitis. 1127 May

Migration of polymorphonuclear neutrophils (PMNL) from the vascular compartment into the pleural space occurs rapidly during the development of parapneumonic effusions. This study investigated the polarized secretion of interleukin (IL)-8 in activated pleural mesothelial cells (PMC) and the migration of PMNL across resting, activated PMC monolayers. Results show that PMC produce IL-8 in a polar manner. When PMC were stimulated with Staphylococcus aureus or IL-1beta at the basal or at the apical surface, significantly (P< .05) more IL-8 was released toward the apical surface. This polarized production of IL-8 was confirmed by in situ hybridization. PMNL migration was higher from the basilar to apical than from the apical to basilar surface of PMC. Neutralizing antibodies against IL-8 and intercellular adhesion molecule (ICAM)-1 significantly (P< .001) blocked PMNL migration across activated monolayers. Thus, during pleural inflammation, PMC regulate the influx of PMNL into the pleural space by polar production of IL-8 and expression of ICAM-1.
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PMID:Polar production of interleukin-8 by mesothelial cells promotes the transmesothelial migration of neutrophils: role of intercellular adhesion molecule-1. 1134 13


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