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)

Airway epithelial cells (AEC) are known to play an integral role in the airway defense mechanism via mucociliary system as well as mechanical barriers. Recent studies further indicate that AEC can produce and release biologically active compounds including lipid mediators, growth factors, endothelin and a variety of cytokines/chemokines important in the pathogenesis of airway disorders. Human bronchial epithelial cells were isolated from normal and diseased states, and purely cultured in hormonally defined, serum-free medium. Culture supernatants of AEC contained detectable amounts of cytokines such as IL-1, IL-6, IL-8, G-CSF and GM-CSF. Proinflammatory cytokines IL-1 and TNFalpha generally upregulated expression and release of these cytokines. Moreover, human bronchial epithelial cells from patients with airway diseases such as asthma showed increased levels of mRNA for the cytokines. AEC are considered to interact with immune and inflammatory cells by direct adhesion as well as by humoral factors including cytokines. For example, eosinophil adhesion to AEC may be an important signal for the activation and degranulation of eosinophils. AEC is also believed to take part in the airway mucosal immunity by interacting with lymphocytes. Finally, AEC may play a crucial role in the processes of airway remodelling found in chronic airway inflammatory diseases. These findings strongly suggest that AEC are actively involved as regulators of airway inflammatory responses playing an important role in the pathogenesis of airway disorders, and become a target for therapeutic intervention.
Int J Mol Med 1998 Feb
PMID:Airway epithelial cells as regulators of airway inflammation (Review). 985 39

Recognition of the ways in which neutrophil behaviour is regulated may be crucial for a full understanding of their role in inflammation and in rheumatoid arthritis. Although it is well established that changes in cytosolic free Ca2+ play a central role in triggering neutrophil responses, only recently has evidence accumulated which points strongly to the existence of two distinct Ca2+ pathways in neutrophils. One pathway is mediated by conventional agonists, such as formylated peptides, IL-8, C5a and PAF, and the other by cross-linking and immobilisation of surface receptors, such as integrins, and the Fc receptors, CD32 and CD16. In this review, we give evidence for these two signalling pathways in neutrophils, highlighting the roles of two Ca2+ storage and release organelles, one centrally located and stationary, and the other peripheral and mobile. We point out the significance of these two routes of Ca2+ signalling for the correct sequence of neutrophil responses, and suggest that aberration of this sequence could result in pathogenic neutrophil activation.
Int J Mol Med 1998 Feb
PMID:Cytosolic Ca2+ signalling in inflammatory neutrophils: implications for rheumatoid arthritis (Review). 985 54

M proteins are receptor proteins and one of the virulence factors of streptococci. M proteins seem to play a role in inflammatory skin disorders such as psoriasis. It is however unknown whether M proteins have a direct influence on proliferative activity of human keratinocytes. In the present study human HaCaT keratinocytes were exposed to M proteins (M1, M3, M5, M12) and the proliferative and proinflammatory response was analyzed. We found a dose-dependent inhibition of keratinocyte proliferation with crude extract of strain M3 4/55. Following affinity chromatography we found inhibitory activity for keratinocyte proliferation with a maximum of 80% at 10-8 M in the M protein. Additionally tested M1 protein preparation showed an inhibitory activity of 55% whereas other M preparations (5 and 12) did not show any effect. In supernatants from HaCaT cultures IL-1alpha, IL-1beta, IL-6, IL-8, TNFalpha and ICAM-1 were measured by ELISA. The levels of IL-8 were high and TNFalpha was upregulated, whereas ICAM-1 was decreased from around 20 ng/ml to almost zero. In contrast to the streptococcal-derived M3 protein preparation the recombinant M3 did not interfere with the proliferation of HaCaT cells. Because neither recombinant M3 protein nor M3 protein purified by ion exchange chromatography on a Q-resource column had any antiproliferative activity on keratinocytes we suggest, that a component different from M3 protein was responsible.
Int J Mol Med 1998 Apr
PMID:Keratinocyte growth inhibition by streptococcal proteins. 985 94

17Beta-hydroxysteroid dehydrogenase (17-HSD) type I is present and active in most breast cancer cell lines where it modulates local estrogen availability. Currently no information is available on its expression in primary cultures. We have quantitatively determined the cellular localisation of both enzyme activity and expression of the 17-HSD type I gene using a series of primary epithelial and stromal cells derived from normal and tumourous breast. Regulation of 17-HSD type I by IL-8 in tumour-derived cultures was also studied. Reversible 17-HSD activity was observed in most samples. In cultures derived from normal breast, the oxidative pathway predominated by up to 51-fold in epithelial and 28-fold in stromal cells. In tumour-derived cultures, the reductive pathway predominated by up to 24-fold in epithelial and 20-fold in stromal cultures, with no preferred direction in the remaining samples. Expression of the 17-HSD type I gene was determined by quantitative RT-PCR. Although this was constitutively expressed by all samples from both tissue types, significantly higher levels of the gene were observed in tumour-derived cultures (P = 0.008, epithelial; P < 0.0001 stromal vs corresponding normal culture). IL-8 upregulated gene expression in epithelial cells but it was downregulated in stroma. This was reflected in 17-HSD type I activity. Thus, 17-HSD type I is constitutively expressed and active in normal and tumourous breast and can be regulated by IL-8.
J Steroid Biochem Mol Biol 1998 Nov
PMID:Activity and gene expression of 17beta-hydroxysteroid dehydrogenase type I in primary cultures of epithelial and stromal cells derived from normal and tumourous human breast tissue: the role of IL-8. 987 85

Epithelial cells actively participate in inflammatory airway disease by liberating mediators such as arachidonate metabolites and cytokines. Inhibition of phosphodiesterases (PDEs) may be a useful anti-inflammatory approach. The PDE isoenzyme pattern and the effects of PDE inhibition on mediator generation were analyzed in primary cultures of human and porcine airway epithelial cells (AEC) and in the bronchial epithelial cell line BEAS-2B. PDE4 and PDE5 were detected in lysates of all cell types studied. In primary cultures of human AEC, the PDE4 variants PDE4A5, PDE4C1, PDE4D2, and PDE4D3 were identified by polymerase chain reaction analysis. Evidence of the recently described PDE7 was obtained by rolipram- insensitive cyclic adenosine monophosphate (cAMP) degradation, and its presence was verified by the demonstration of PDE7 messenger RNA. Primary cultures of human airway epithelium also expressed PDE1. Enhanced epithelial cAMP levels, induced by forskolin and PDE4 inhibition, increased formation of prostaglandin E2 (PGE2), but not of interleukin (IL)-8 or 15-hydroxyeicosatetraenoic acid (15-HETE) in airway epithelial cells. Increased cyclic guanosine monophosphate levels in these cells provoked by sodium nitroprusside and the PDE5 inhibitor zaprinast reduced the PGE2 synthesis, whereas 15-HETE and IL-8 formation were unchanged. The data suggest that PDE isoenzymes are important in airway inflammation and that PDE inhibitors exert anti-inflammatory effects by acting on AEC.
Am J Respir Cell Mol Biol 1999 Feb
PMID:Identification and function of cyclic nucleotide phosphodiesterase isoenzymes in airway epithelial cells. 992 21

Approximately 15 different alpha, or CXC, chemokines have thus far been isolated from 11 species of mammals. Among the best studied chemokines are the 12 human proteins that are encoded by 11 paralogous genes. In order to better understand the evolution and function of this group of genes, we isolated and characterized six novel GRO and GRO-related cDNA sequences from the cow (Bos taurus), the sheep (Ovis aries), the rabbit (Oryctolagus cuniculus), and the guinea pig (Cavia porcellus). The amino acid sequence of the diverged guinea pig GRO or KC gene is only 50%-60% similar to presumed orthologs from other species, while the sheep and cow GRO proteins are 90%-99% similar to each other. The presence of multiple GRO genes in the cow, the rabbit, and the sheep is consistent with what has been observed for humans. Phylogenetic analyses of amino acid sequences from 44 proteins indicate that genes orthologous to many of the 11 known from humans exist in other species. One such gene, interleukin 8, or IL8, has been isolated from nine species, including the rodent guinea pig; however, this gene is absent in the rat and the mouse, indicating a unique gene loss event in the rat/mouse (muroid rodent) lineage. The KC (or MIP2) gene of rodents appears to be orthologous to the GRO gene found in other taxonomic orders. Combined evidence from different sources suggests that IP10 and MIG share sister taxon relationships on the evolutionary tree, while the remaining paralogous genes represent independent lineages, with limited evidence for kinship between them. This observation indicates that these genes originated nearly contemporaneously via a series of gene duplication events. Relative-rate tests for synonymous and nonsynonymous nucleotide substitutions in the KC and IL8 genes did not detect rate heterogeneity; however, there are several notable features regarding the IL8 genes. For example, the IL8 proteins from two Old World monkeys are as similar to one another as they are to the IL8 protein from humans, and all observed nucleotide differences between the IL8 genes of the two monkeys cause amino acid changes; in other words, there are no synonymous differences between them.
Mol Biol Evol 1999 Feb
PMID:Isolation of novel GRO genes and a phylogenetic analysis of the CXC chemokine subfamily in mammals. 1002 86

This study examined the role of P and type 1 fimbriae for neutrophil migration across Escherichia coli-infected uroepithelial cell layers in vitro and for neutrophil recruitment to the urinary tract in vivo. Recombinant E. coli K-12 strains differing in P or type 1 fimbrial expression were used to infect confluent epithelial layers on the underside of transwell inserts. Neutrophils were added to the upper well, and their passage across the epithelial cell layers was quantified. Infection with the P- and type 1-fimbriated recombinant E. coli strains stimulated neutrophil migration to the same extent as a fully virulent clinical E. coli isolate, but the isogenic non-fimbriated vector control strains had no stimulatory effect. The enhancement of neutrophil migration was adhesion dependent; it was inhibited by soluble receptor analogues blocking the binding of P fimbriae to the globoseries of glycosphingolipids or of type 1 fimbriae to mannosylated glycoprotein receptors. P- and type 1-fimbriated E. coli triggered higher interleukin (IL) 8 secretion and expression of functional IL-8 receptors than non-fimbriated controls, and the increase in neutrophil migration across infected cell layers was inhibited by anti-IL-8 antibodies. In a mouse infection model, P- or type 1-fimbriated E. coli stimulated higher chemokine (MIP-2) and neutrophil responses than the non-fimbriated vector controls. The results demonstrated that transformation with the pap or fim DNA sequences is sufficient to convert an E. coli K-12 strain to a host response inducer, and that fimbriation enhances neutrophil recruitment in vitro and in vivo. Epithelial chemokine production provides a molecular link between the fimbriated bacteria that adhere to epithelial cells and tissue inflammation.
Mol Microbiol 1998 Nov
PMID:Role of fimbriae-mediated adherence for neutrophil migration across Escherichia coli-infected epithelial cell layers. 1009 21

The facultative intracellular bacterium Listeria monocytogenes is an invasive pathogen that crosses the vascular endothelium and disseminates to the placenta and the central nervous system. Its interaction with endothelial cells is crucial for the pathogenesis of listeriosis. By infecting in vitro human umbilical vein endothelial cells (HUVEC) with L. monocytogenes, we found that wild-type bacteria induced the expression of the adhesion molecules (ICAM-1 and E-selectin), chemokine secretion (IL-8 and monocyte chemotactic protein-1) and NF-kappa B nuclear translocation. The activation of HUVEC required viable bacteria and was abolished in prfA-deficient mutants of L. monocytogenes, suggesting that virulence genes are associated with endothelial cell activation. Using a genetic approach with mutants of virulence genes, we found that listeriolysin O (LLO)-deficient mutants inactivated in the hly gene did not induce HUVEC activation, as opposed to mutants inactivated in the other virulence genes. Adhesion molecule expression, chemokine secretion and NF-kappa B activation were fully restored by a strain of Listeria innocua transformed with the hly gene encoding LLO. The relevance in vivo of endothelial cell activation for listerial pathogenesis was investigated in transgenic mice carrying an NF-kappa B-responsive lacZ reporter gene. NF-kappa B activation was visualized by a strong lacZ expression in endothelial cells of capillaries of mice infected with a virulent haemolytic strain, but was not seen in those infected with a non-haemolytic isogenic mutant. Direct evidence that LLO is involved in NF-kappa B activation in transgenic mice was provided by injecting intravenously purified LLO, thus inducing stimulation of NF-kappa B in endothelial cells of blood capillaries. Our results demonstrate that functional listeriolysin O secreted by bacteria contributes as a potent inflammatory stimulus to inducing endothelial cell activation during the infectious process.
Mol Microbiol 1999 Mar
PMID:Listeriolysin O-dependent activation of endothelial cells during infection with Listeria monocytogenes: activation of NF-kappa B and upregulation of adhesion molecules and chemokines. 1020 44

Interleukin (IL)-1beta is produced primarily by activated mononuclear phagocytic cells in the lung airway and functions as a potent proinflammatory cytokine. Release of IL-1beta in the airway microenvironment induces the production of proinflammatory factors from parenchymal airway cells, including IL-8. To study the regulation of lung epithelial cell responsiveness to IL-1beta, the human type II-like airway epithelial cell line A549 and primary normal human bronchial epithelial (NHBE) cells were assayed for IL-1-specific response modifiers. Specifically, the IL-1 type I receptor (IL-1RI), IL-1 type II receptor (IL-1RII), IL-1 receptor accessory protein (IL-1RAcP), and IL-1 receptor antagonist (IL-1Ra) were analyzed. Constitutive expression of IL-1RI, IL-1RAcP, and IL-1Ra was detected in both immortalized and primary human airway epithelial cells. Interestingly, a complete absence of IL-1RII expression was demonstrated under all study conditions in both A549 and NHBE cells. Both cell types were responsive to IL-1beta at concentrations as low as 50 to 500 pg/ml when measured by IL-8 release into cell supernatants. IL-1beta-induced chemokine production and release were inhibited by a 10- to 1,000-fold molar excess of recombinant IL-1RII or IL-1Ra, whereas IL-1RI was a less effective inhibitor. On the basis of our results, we propose that human lung epithelial cells lack the ability to downregulate IL-1beta activity extracellularly because of an inability to express IL-1RII. Release of extracellular IL-1 inhibitors, including soluble IL-1Ra and soluble IL-1RII, by other inflammatory cells present in the airway may be critical for regulation of IL-1beta activity in the airway microenvironment.
Am J Respir Cell Mol Biol 1999 May
PMID:Extracellular regulation of interleukin (IL)-1beta through lung epithelial cells and defective IL-1 type II receptor expression. 1022 66

There is evidence that asthma and other allergic diseases are increasing and air pollution has been considered an important contributing factor to this observation. Using a specially designed organ culture system, we examined the influence of ozone (0.06 to 0. 2 ppm) and nitrogen dioxide (NO2, 200 and 800 micrograms/m3) on nasal mucosa exposed for 24 h. Tissue was obtained from 105 patients undergoing surgical therapy (septoplasty and reduction of the inferior turbinates) for chronic nasal obstruction. The histamine content in the culture medium of ozone- and NO2-exposed samples was significantly elevated compared with the control cultures. This elevation was correlated with the number of degranulated mast cells in the tissue determined by histomorphometry (P < 0.001). Moreover, the cytokines interleukin (IL)-1beta (P < 0.05), IL-6 (P < 0.01), IL-8 (P < 0.001), and tumor necrosis factor-alpha (TNF-alpha, P < 0. 001) were significantly increased (ozone 0.1 ppm). Furthermore, we found significant increases in the release of IL-4, IL-6, IL-8, and TNF-alpha of ozone-exposed (0.1 ppm) samples of atopic versus nonatopic patients and to a lesser extent for histamine following exposure to 0.15 ppm ozone. These results indicate that low ozone concentrations and NO2 lead to an inflammation of human nasal mucosa in vitro and that priming factors such as atopy or preexisting inflammation do increase the sensitivity to ozone and NO2. This organ culture system proved to be a good experimental design for studying pathophysiologic alterations of human nasal mucosa under different experimental conditions (e.g., air pollutants).
Am J Respir Cell Mol Biol 1999 May
PMID:Influence of ozone and nitrogen dioxide on histamine and interleukin formation in a human nasal mucosa culture system. 1022 72


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