Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acquisition of Pseudomonas aeruginosa in the airways of patients with cystic fibrosis (CF) is the initial event leading to bronchiectasis and lung disease. Although the host factors that permit initial airway colonization are largely unknown, recent studies suggest that secretion of interleukin (IL)-8 by airway epithelia and local recruitment of neutrophils is the final pathway in a pulmonary cytokine network. To determine whether differences in cytokine production exist between normal and CF airway epithelia, secretion of immunoreactive IL-8 and IL-10 as well as specific messenger RNA (mRNA) abundance were compared in airway epithelia expressing normal and mutant CF transmembrane regulator. After induction with IL-1beta, a CF airway cell line engineered to express the wild-type CF gene (CFT1-LCFSN) secreted significantly more immunoreactive IL-8 than did its isogenic parent that expressed the mutant CF gene (CFT1) or an isogenic vector control line (CFT1-LC3). Further studies with the three related cell lines demonstrated that expression of CFT1-LCFSN was associated with a significant increase in uninduced secretion of immunoreactive IL-8 as well as a 10- to 20-fold increase in IL-8 mRNA abundance when compared with the isogenic lines expressing the mutant gene. IL-1beta induction and intracellular accumulation of IL-8 appeared to be unaffected by CF genotype. These studies suggest that IL-8 secretion by CF airway epithelial cells is defective and may contribute to Pseudomonas persistence in the CF airway. Further studies are needed to confirm this difference in other cell lines and determine the linkage between IL-8 production and CF gene expression.
Am J Respir Cell Mol Biol 1999 May
PMID:Reduced interleukin-8 production by cystic fibrosis airway epithelial cells. 1022 79

FK506, a potent immunosuppressant, has attracted attention for its potential effectiveness in allergic diseases. Although eosinophils are believed to be one of the important effector cells at the site of allergic inflammation, there have been few reports about the direct effect of FK506 on eosinophils. In the present study, we evaluated if FK506 had any effect on the production of IL-8, one of the important chemokines for a variety of inflammatory cells, from human peripheral eosinophils. Purified eosinophils constitutively released IL-8, which was increased with calcium ionophore (10(-6) M). FK506 showed a dose-dependent suppressive effect on IL-8 production by eosinophils stimulated with calcium ionophore, but showed no effect on unstimulated cells. Evaluation of IL-8 mRNA levels by reverse transcription and polymerase chain reaction demonstrated that FK506 suppressed IL-8 gene expression only in activated eosinophils. FK506 further showed a suppressive effect on eotaxin and MCP-1 release from eosinophils. These findings suggested that FK506 might prevent infiltration of inflammatory cells such as eosinophils by, at least in part, inhibiting chemokine release from eosinophils.
Mol Cell Biol Res Commun 1999 Apr
PMID:A potent immunosuppressant FK506 inhibits IL-8 expression in human eosinophils. 1032 81

Cervical ripening is a cytokine-triggered process with substantial remodelling of the cervical extracellular matrix. Interleukin-8 (IL-8) is an important cytokine in cervical maturation. Glycosaminoglycans are also included in this process, but their role in not clearly understood. The effects of heparan sulphate (HS), hyaluronic acid (HA), IL-8, HS + IL-8 and HA + IL-8 on biochemical properties of the cervix were examined in non-pregnant rabbits. The changes in vascular pattern with collagen structure of the cervices and immunohistochemical studies, together with the relative collagen concentrations, were determined. A reduction in relative collagen concentration was significant after HS + IL-8, IL-8 and HA + IL-8 treatment (all P < 0.0001). Gel electrophoresis analysis showed that IL-8 bound preferentially to HS than to HA. Neutrophils were significantly increased in number (P < 0.0001) and located predominantly beneath the glandular epithelium and around the blood vessels after HS + IL-8 treatment. HS + IL-8 treatment caused cervices to increase their water content and become oedematous. The collagen fibres were considerably dissociated, the interfibrillar spaces markedly dilated, and the blood vessels notably increased and dilated. We conclude that binding to HS enhances the activity of IL-8 in inducing cervical maturation.
Mol Hum Reprod 1999 Mar
PMID:Binding of interleukin-8 to heparan sulphate enhances cervical maturation in rabbits. 1033 61

We have used the Stamper-Woodruff frozen-section assay (FSA) to characterize the integrin and activation steps involved in adhesion of peripheral blood eosinophils and neutrophils to nasal polyp endothelium (NPE). Eosinophil and neutrophil adhesion was significantly inhibited by monoclonal antibodies (mAbs) against CD18 (beta2) and CD11a-c. Eosinophil adhesion was also inhibited to a lesser extent by mAbs against CD29 (beta1), CD49d (alpha4), and vascular cell adhesion molecule-1. The involvement of integrins raised the possibility of an activation step being involved in the adhesion process. Although stimulation of the cells with granulocyte macrophage colony-stimulating factor (GM-CSF) before the assay failed to modulate adhesion, binding was inhibited by up to 50% by treatment of the leukocytes with azide. In addition, neutrophil adhesion was completely abrogated by pertussis toxin (PT) and inhibited by about 50% by the platelet-activating factor antagonist WEB 2086 and antibodies against interleukin (IL)-8 and the two IL-8 receptors IL8RA and IL8RB (C-X-CR1 and -CR2). In contrast, eosinophil adhesion was unaffected by PT, WEB 2086, or anti-IL8R mAbs. mAbs against CCR-3, IL-3, IL-5, and GM-CSF also had no effect. This study demonstrates that eosinophil and neutrophil adhesion to NPE in the FSA conforms to the multistep paradigm for leukocyte adhesion and can be used to model the molecular basis for adhesion to endothelium in the context of chronic inflammatory disease. Using this assay, we have observed significant differences in integrin usage between eosinophils and neutrophils and a striking difference in the mechanism of integrin activation. These differences could explain, in part, the preferential accumulation of eosinophils in diseases such as asthma.
Am J Respir Cell Mol Biol 1999 Jun
PMID:Characterization of the integrin and activation steps mediating human eosinophil and neutrophil adhesion to chronically inflamed airway endothelium. 1034 Sep 44

Although preimplantation embryo and decidual cells secrete significant amounts of platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF); its precise function in early pregnancy has yet to be established. To investigate the effect of PAF on cytokine synthesis, we measured the cytokine concentration in the culture media of two human cell lines: normal endometrial stromal cells (ESC) and endometrial stromal sarcoma cells (MaMi), following stimulation with a non-metabolized PAF analogue, carbamyl-PAF (C-PAF). Enzyme-linked immunosorbent assays were used to measure five cytokines: interleukin (IL)-6, IL-8, macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein-1alpha (MIP-1alpha) and tumour necrosis factor-alpha (TNF-alpha). We also evaluated the mRNA expression for IL-6 and IL-8 in ESC after C-PAF stimulation using Northern blot analysis. Non-stimulated ESC and MaMi cells both secreted IL-6, IL-8, and M-CSF, but not MIP-1alpha or TNF-alpha. The concentrations of IL-6, IL-8, M-CSF, MIP-1alpha, and TNF-alpha in the culture media of both cell lines increased in parallel with increasing amounts of C-PAF. C-PAF stimulated IL-6 and IL-8 transcription in ESC. These results suggest that PAF secretion by decidual tissues and developing embryos may induce cytokine synthesis by the ESC, as part of the cytokine network in the feto-maternal unit. An increase in the local cytokine concentration may be an important factor in the maintenance of early stages of gestation.
Mol Hum Reprod 1999 Jun
PMID:Platelet-activating factor stimulates cytokine production by human endometrial stromal cells. 1034 Oct 2

We evaluated the ability of eosinophil granule major basic protein (MBP) to stimulate interleukin (IL)-8 production by neutrophils. MBP over the concentration range of 0.1 to 10 microM stimulated the release of up to approximately 8 ng/ml IL-8. Incubation with 2 microM MBP showed that, after a 1 h lag, the level of IL-8 release increased with time for approximately 10 h. At the 2 microM concentration, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase did not stimulate significant levels of IL-8 production. MBP stimulated 2-fold increases in IL-8 messenger RNA (mRNA) after 1 and 3 h of incubation, which were blocked by pretreatment with actinomycin D. However, stimulation with MBP did not produce an increase in the binding activity of nuclear factor (NF)-kappaB or activator protein-1. No NF-IL-6 binding activity was detected in the same nuclear extracts. In addition, stimulation with MBP prolonged the stability of IL-8 mRNA. MBP also induced transient increases in mRNA for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, but did not stimulate the release of either chemokine. These findings indicate that MBP is selective among the eosinophil granule proteins as a stimulus for neutrophil IL-8 release and, further, that stimulation of neutrophil IL-8 release by MBP involves both transcriptional and posttranscriptional regulation. We postulate that MBP-induced release of IL-8 by neutrophils may contribute to the pathophysiology of acute asthma and other inflammatory lung diseases.
Am J Respir Cell Mol Biol 1999 Aug
PMID:Stimulation of neutrophil interleukin-8 production by eosinophil granule major basic protein. 1042 6

Complement-derived anaphylatoxin C5a is a glycopolypeptide important in the regulation of inflammation. Previously, we have shown that C5a receptors (C5aR) are constitutively expressed on human bronchial epithelial cells (HBECs) grown in culture. We have also shown that the expression of C5aR is increased upon exposure of HBECs to 5% cigarette smoke extract (CSE), and that this subtoxic dose of CSE significantly enhances C5a-stimulated interleukin (IL)-8 release. To determine the intracellular signaling pathway of CSE + C5a-mediated IL-8 release, we assayed protein kinase C (PKC) activity of HBECs after exposing the cells to CSE and/or C5a. No increase in PKC activity was observed when HBECs were treated with 50 nM C5a for various times. However, PKC activity was increased by 2- to 3-fold in HBECs stimulated with 5% CSE for 1 h, as compared with cells incubated with medium only. No additional increase in PKC was observed when HBECs were treated with CSE and C5a together. When HBECs were pretreated with the PKC-specific inhibitor calphostin C (1 microM), no CSE-mediated PKC activation was observed. We then correlated PKC activation with IL-8 release in the same cells. Although HBECs required stimulation by both CSE and C5a to release maximal levels of IL-8, preincubation of CSE-stimulated HBECs with calphostin C inhibited IL-8 release by CSE + C5a. These results suggest that PKC activation by CSE alone does not result in IL-8 release, but that CSE-stimulated PKC activation is required for C5a-mediated IL-8 release from HBECs.
Am J Respir Cell Mol Biol 1999 Aug
PMID:Protein kinase C activation is required for cigarette smoke-enhanced C5a-mediated release of interleukin-8 in human bronchial epithelial cells. 1042 13

Interleukin-8 (IL-8) is a chemotactic and activating factor for neutrophils which play important roles in host defence mechanisms. The human placenta constitutively produces IL-8 during pregnancy and enhances its production in chorioamnionitis. The present study was designed to investigate in vitro the regulatory mechanism for IL-8 production in the placentas in normal and inflammatory states. Placental cells produced IL-8 in a dose-dependent fashion when stimulated with lipopolysaccharide (LPS). The purified trophoblasts showed significantly higher IL-8 production than untreated placental cells. The expression of IL-8 gene in the trophoblasts in the third trimester was observed by reverse transcription-polymerase chain reaction (RT-PCR). The placental cells also release IL-8 in a dose-dependent manner, in response to r-(recombinant) IL-1alpha and tumour necrosis factor (TNF)-alpha, but not rIL-6. Moreover, LPS-activated placental cells spontaneously produced a much larger amount of IL-8 and showed increased responses to rIL-1alpha and TNF-alpha. It may, therefore, be proposed that placental cells with multiple endocrine functions exert immunological functions by constitutive production of IL-1 and TNF-alpha, which stimulate placental IL-8 release. This cytokine cascade in the placenta may be augmented by LPS in chorioamnionitis, thereby potentiating the feto-maternal defence mechanisms against infection.
Mol Hum Reprod 1999 Sep
PMID:Human placental cells show enhanced production of interleukin (IL)-8 in response to lipopolysaccharide (LPS), IL-1 and tumour necrosis factor (TNF)-alpha, but not to IL-6. 1046 Feb 29

In an earlier study, we showed that a recombinant adenovirus vector with deletions in the E1 and E3 regions of the viral genome (AV1LacZ4) induces expression of interleukin (IL)-8 in A549 cells (a human respiratory cell line). IL-8 can be induced through several pathways, including activation by IL-1. We tested the hypothesis that the induction of IL-8 by the AV1LacZ4 adenovirus is accomplished by means of the IL-1/IL-8 activation pathway, which could be blocked by IL-1 receptor antagonist (IRAP). Viral infections of A549 cells were performed at a multiplicity of infection (MOI) of 50 in the presence and absence of IRAP (50 ng/ml). A549 cells were also stimulated with tumor necrosis factor (TNF)-alpha (100 ng/ml), a known stimulant of IL-8, in the presence and absence of IRAP. IL-8 expression was evaluated by Northern blot analysis and enzyme-linked immunosorbent assay. Levels of IL-8 protein and messenger RNA (mRNA) were greater in the infected cells than in the uninfected ones at 24, 48, and 96 h (P < 0.01). Virus-infected cells treated with IRAP expressed 75% less IL-8 mRNA and protein (P < 0.01) than did untreated cells, whereas IRAP pretreatment of TNF-alpha-stimulated cells did not affect IL-8 production. IL-1 production by the virus-infected cells was detectable by concentration of the supernatants and reverse transcription-polymerase chain reaction. We conclude that IL-8 is produced by virus vector-infected cells, partly through IL-1 activation that can be downregulated by IRAP.
Am J Respir Cell Mol Biol 1999 Sep
PMID:Interleukin-1 receptor antagonist inhibits interleukin-8 expression in A549 respiratory epithelial cells infected in vitro with a replication-deficient recombinant adenovirus vector. 1046 Jul 56

Polymorphonuclear leukocytes (PMN) and eosinophils (Eos) are important cellular participants in a variety of acute and chronic inflammatory reactions in the airway. Histologic evidence has implicated direct interactions between these two subsets of leukocytes and airway epithelial cells during inflammation. A comprehensive characterization and comparison of physiologic stimuli and adhesion molecule involvement in granulocyte-epithelial-cell interactions done with nontransformed human airway epithelial cells has not been reported. We therefore examined the regulation and biochemical mechanisms governing granulocyte-epithelial-cell adhesion, using either purified PMN or Eos and primary cultures of human bronchial epithelial cells (HBECs). We investigated the involvement of a number of proinflammatory signals associated with allergic and nonallergic airway inflammation, as well as the contribution of several epithelial and leukocyte adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and members of the beta(1), beta(2), and beta(7) integrin families. ICAM-1 was expressed at low levels on cultured HBECs and was markedly upregulated after stimulation with interferon (IFN)-gamma or, to a lesser extent, with tumor necrosis factor (TNF)-alpha or interleukin (IL)-1. VCAM-1 was not present on resting HBECs, and was not upregulated after stimulation with IFN-gamma, IL-1, IL-4, or TNF-alpha. PMN adhesion to HBECs could be induced either through activation of PMN with IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), or C5a, but not with IL-5 or by preactivation of HBECs with TNF-alpha or IFN-gamma. Blocking antibody studies indicated that PMN-HBEC adherence depended on beta(2) integrins, primarily alpha(M)beta(2) (Mac-1). Adherence of Eos to HBECs could be induced through activation of Eos with IL-5, GM-CSF, or C5a, but not with IL-8 or by prior activation of HBECs with TNF-alpha of IFN-gamma. Maximal adhesion of Eos and PMN required pretreatment of HBECs with either TNF-alpha or IFN-gamma in addition to leukocyte activation. Adherence of Eos to unstimulated HBECs was mediated through both beta(1) and beta(2) integrins, whereas adhesion of Eos to activated HBECs was dominated by beta(2) integrins. Adhesion of both Eos and PMN was inhibited by treatment of HBECs with blocking antibodies to ICAM-1. Differential utilization of beta(1) and beta(2) integrins by Eos, depending on the activation state of the epithelium, is a novel finding and may affect activation and/or recruitment of Eos in airway tissue. Mechanisms of adhesion of HBECs to Eos and PMN, as evidenced by the different responsiveness of the two latter types of cells to IL-8 and IL-5, may account for a prevalence of Eos over PMN in certain airway diseases.
Am J Respir Cell Mol Biol 1999 Sep
PMID:Mechanisms and regulation of polymorphonuclear leukocyte and eosinophil adherence to human airway epithelial cells. 1046 Jul 60


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