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)

The chicken gene, 9E3/CEF4, is a small inducible cytokine highly homologous to human IL-8 and gro alpha. It is overexpressed during wound healing and in the tissues around tumours induced by Rous sarcoma virus. More is known about the expression of 9E3 in vivo than any other of the small cytokines, yet little is known about its biochemical characteristics and functions. Here we report on some of the biochemical properties of the 9E3 gene product, the kinetics of protein secretion, the post-secretory processing of the protein, and on its association with ECM molecules. The protein: (1) is synthesized and secreted in < 10 min; (2) is not glycosylated and does not bind heparin with high affinity; (3) is secreted as a 9 kDa form and is processed to a 6-7 kDa form by plasmin, an enzyme released at wound sites and produced in association with tumours; (4) the small form binds to interstitial collagen, laminin and to a lesser extent to proteoglycan, and does not bind to collagen IV or fibronectin. This is the most rapidly secreted protein yet described in eukaryotic cells and is the first of the small inducible cytokines to be found to associate with ECM molecules other than glycosaminoglycans. Our results suggest that, given the appropriate stimulus, the level of the 9E3 cytokine could be elevated very rapidly, resulting in similarly rapid biological responses. The different modes of availability of the two forms of the molecule suggest that the two isoforms may play different roles in vivo.
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PMID:The 9E3/CEF4 cytokine: kinetics of secretion, processing by plasmin, and interaction with extracellular matrix. 881 41

Ulcerative colitis involving primarily the mucosa of the colon and rectum is a diffuse and nonspecific inflammatory disease. Immunocompetent cells infiltrating in the inflammed mucosa are mainly lymphocytes, macrophages and neutrophils. These activated cells produce proinflammatory cytokines such as IL-1, IL-6, IL-8 and TNF alpha and inflammatory activators such as PAF, leukotriene, prostaglandins, free radicals and proteases, resulting in acute on chronic states. Non-surgical therapy for ulcerative colitis includes basic medical therapy with sulfasulphapyridine, 5-ASA, corticosteroids and immune suppressive drugs as well as new therapies, which are leukocytapheresis, granulocytapheresis, anticytokine therapy with antiTNF alpha monoclonal antibody, IL-1ra and IL-10, intravenous treatment of massive immunoglobulins and transdermal nicotine therapy.
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PMID:[Non-surgical therapy for ulcerative colitis]. 916 97

The chemokine cCAF (&cmacr;hicken &Cmacr;hemotactic and Angiogenic &Fmacr;actor), is the product of the 9E3/CEF4 gene. Its name reflects the biological properties of the protein: chemotactic and angiogenic. This CXC chemokine is highly homologous to human IL-8, both at the protein and gene level. Molecular modeling based on the known structure of IL-8 shows that the structure of cCAF is very similar to that of other CXC chemokines. Regulation of expression occurs both at the transcriptional and post-transcriptional levels. The cCAF protein is secreted very rapidly as a 9kDa molecule and can be cleaved in the N-terminus after secretion to produce a smaller form ( approximately 7kDa) that binds to ECM molecules. Plasmin, an enzyme present in the early stages of wound healing and in tumor stroma, cleaves the 9kDa to the 7kDa form. The biological properties of this chemokine and its patterns of expression in vivo strongly suggest that cCAF plays important roles in traumatic and pathological conditions.
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PMID:The chicken Chemotactic and Angiogenic Factor (cCAF), a CXC chemokine. 1131 11

Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative endogenous braking signals for inflammation in the gastrointestinal tract and other organs. Aspirin triggers the production of 15-epimers during cell-cell interaction in a cytokine-primed milieu, and aspirin-triggered 15-epi-5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) may contribute to the bioactivity profile of this prototype nonsteroidal anti-inflammatory drug in vivo. We determined the effect of LXA(4), 15-(R/S)-methyl-11,12-dehydro-LXA(4) methyl ester (15-(R/S)-methyl-LXA(4)), and stable analogs of LXA(4) on TNF-alpha-stimulated neutrophil-enterocyte interaction in vitro and TNF-alpha-stimulated chemokine release, changes in mucosal architecture, and enterocyte apoptosis in cytokine-activated intact human colonic mucosa ex vivo. LXA(4), 15-(R/S)-epi-LXA(4), and 16-phenoxy-11,12-dehydro-17,18,19,20-tetranor-LXA(4) methyl ester (16-phenoxy-LXA(4)) inhibited TNF-alpha-stimulated neutrophil adherence to epithelial monolayers at nanomolar concentrations. In parallel experiments involving human colonic mucosa ex vivo, LXA(4)potently attenuated TNF-alpha-stimulated release of the C-X-C chemokine IL-8, and the C-C chemokines monocyte-chemoattractant protein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic mucosa to TNF-alpha induced disruption of mucosa architecture and enhanced colonocyte apoptosis via a caspase-3-independent mechanism. Prior exposure of the mucosa strips to 15-(R/S)-methyl-LXA(4) attenuated TNF-alpha-stimulated colonocyte apoptosis and protected the mucosa against TNF-alpha-induced mucosal damage. In aggregate, our data demonstrate that lipoxins and aspirin-triggered 15-epi-LXA(4) are potent antagonists of TNF-alpha-mediated neutrophil-enterocyte interactions in vitro, attenuate TNF-alpha-triggered chemokine release and colonocyte apoptosis, and are protective against TNF-alpha-induced morphological disruption in human colonic strips ex vivo. Our observations further expand the anti-inflammatory profile of these lipoxygenase-derived eicosanoids and suggest new therapeutic approaches for the treatment of inflammatory bowel disease.
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PMID:Lipoxin A(4) and aspirin-triggered 15-epi-lipoxin A(4) antagonize TNF-alpha-stimulated neutrophil-enterocyte interactions in vitro and attenuate TNF-alpha-induced chemokine release and colonocyte apoptosis in human intestinal mucosa ex vivo. 1150 22

To gain insight into the transformation of epidermal cells into squamous carcinoma cells (SCC), we compared the response to ultraviolet B radiation (UVB) of normal human epidermal keratinocytes (NHEK) versus their transformed counterpart, SCC, using biological and molecular profiling. DNA microarray analyses (Affymetrix), approximately 12000 genes) indicated that the major group of upregulated genes in keratinocytes fall into three categories: (i). antiapoptotic and cell survival factors, including chemokines of the CXC/CC subfamilies (e.g. IL-8, GRO-1, -2, -3, SCYA20), growth factors (e.g. HB-EGF, CTGF, INSL-4), and proinflammatory mediators (e.g. COX-2, S100A9), (ii). DNA repair-related genes (e.g. GADD45, ERCC, BTG-1, Histones), and (iii). ECM proteases (MMP-1, -10). The major downregulated genes are DeltaNp63 and PUMILIO, two potential markers for the maintenance of keratinocyte stem cells. NHEK were found to be more resistant than SCC to UVB-induced apoptosis and this resistance was mainly because of the protection from cell death by secreted survival factors, since it can be transferred from NHEK to SCC cultures by the conditioned medium. Whereas the response of keratinocytes to UVB involved regulation of key checkpoint genes (p53, MDM2, p21(Cip1), DeltaNp63), as well as antiapoptotic and DNA repair-related genes - no or little regulation of these genes was observed in SCC. The effect of UVB on NHEK and SCC resulted in upregulation of 251 and 127 genes, respectively, and downregulation of 322 genes in NHEK and 117 genes in SCC. To further analyse these changes, we used a novel unsupervised coupled two-way clustering method that allowed the identification of groups of genes that clearly partitioned keratinocytes from SCC, including a group of genes whose constitutive expression levels were similar before UVB. This allowed the identification of discriminating genes not otherwise revealed by simple static comparison in the absence of UVB irradiation. The implication of the changes in gene profile in keratinocytes for epithelial cancer is discussed.
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PMID:Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer. 1277 51

We studied the levels of proinflammatory cytokines in the blood plasma of patients with acute coronary syndrome (ACS) when using antiaggregants differing in mechanisms of action. Cytokines were measured with application of solid phase enzyme immunoassay. The ACS patients were randomised into two groups. Group 1 received aspirin in a dose of 162.5 mg/day, group 2 received tienopyridines: tiklid 250 mg twice a day or plavix (clopidogrel) 75 mg/day. On admission to hospital, the patients had high levels of such proinflammatory cytokines as IL-1 beta, IL-8, TNF alpha which significantly lowered on treatment days 20 and 90. Aspirin reduced the cytokines levels in blood plasma more effectively than tienopyridines.
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PMID:[Effects of antiaggregants on concentration of plasma cytokines in patients with acute coronary syndrome]. 1287 86

Atherosclerosis and its complications such as stroke, myocardial infraction and peripheral vascular disease, remain the major causes of morbidity and mortality in the world. Studies have showed that chemokines and adhesion molecules are involved in causing atherosclerosis by promoting directed migration of inflammatory cells. Monocyte chemoattractant protein-1 (MCP-1) is one of the key factors critical for the initiating and developing of atherosclerotic lesions. IL-8, a CXC chemokine, stimulates neutrophil chemotaxis. Aspirin is the most common drug used to prevent the complications of atherosclerosis such as stroke and coronary heart disease. In this study, we found that aspirin inhibited TNF-alpha (10 ng/ml)-induced MCP-1 and IL-8 expression at the RNA and protein levels in human umbilical vein endothelial cells (HUVECs), monocyte adhesion and transmigration, and that its inhibitory effects were not due to decreased HUVEC viability as assessed by MTT test. Aspirin at the dose as low as 10 microg/ml significantly inhibited the release of TNF-stimulated MCP-1 by 29.1% (P = 0.008) and IL-8 by 26.9% (P = 0.0146) as compared to TNF-stimulated release. Antibodies pretreatment were likely to decrease the production of MCP-1 (P < 0.0001) and IL-8 (P < 0.0001). Furthermore, aspirin (10 microg/ml) inhibited U937 cell adhesion by a 13.4% (P = 0.0119) inhibition as compared to TNF-stimulated alone. Finally, at higher concentration, aspirin also inhibited U937 migration to HUVEC by 89.1% (P = 0.0475) as compared to TNF-stimulated alone. These results in our study suggest that aspirin inhibits TNF-alpha stimulated MCP-1 and IL-8 release in HUVECs, for its additional therapeutic effects of aspirin in causing atherosclerosis.
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PMID:Aspirin inhibits monocyte chemoattractant protein-1 and interleukin-8 expression in TNF-alpha stimulated human umbilical vein endothelial cells. 1513 50

We have demonstrated recently that PTHrP is upregulated in pancreatic adenocarcinoma and that the ECM exerts regulatory control, at least in part, over PTHrP expression. In our present study, we examined the potential signaling interactions between these 2 pathways. Our results demonstrate that, under serum-free conditions, adhesion of FG pancreatic adenocarcinoma cells on Fn is mediated by the alpha5beta1 integrin, whereas adhesion to Type I collagen is mediated by the alpha2beta1 integrin. alpha5beta1 integrin-mediated adhesion to Fn results in a phenotype that includes a reduction in cell proliferation, increased E-cadherin localization in cell-cell contacts, increased beta-catenin localization throughout the cell, inhibition of haptokinetic cell migration, and increased expression of PTHrP, IL-6 and IL-8 relative to alpha2beta1 integrin-mediated adhesion on Type I collagen. A phosphoprotein immunoblotting screen of FG pancreatic cancer cells grown on either Fn or Type I collagen indicates that GSK3 and PKB/Akt are differentially phosphorylated on these 2 substrates. These results implicate GSK3 and PKB/Akt in the integrin-mediated regulation of PTHrP, IL-6 and IL-8 in pancreatic cancer.
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PMID:GSK3 and PKB/Akt are associated with integrin-mediated regulation of PTHrP, IL-6 and IL-8 expression in FG pancreatic cancer cells. 1560 21

The small GTPases of the Rho family are key intermediates in cellular signalling triggered by activated cell-adhesion receptors. In this study, we took advantage of RNA interference (RNAi) using small interfering RNAs (siRNAs) to define the roles of the best-characterized members of the RhoGTPase family, RhoA, Rac1 and Cdc42, in the control of MMP-1, MMP-2 and type-I-collagen expression in normal human skin fibroblasts (HSFs). A specific and long-lasting repression, up to 7 days after transfection, of the three GTPases was achieved by transient transfection of specific siRNA. The silencing of Cdc42, but not that of RhoA or Rac1, induced a 15-fold increase in MMP-1 secretion. This upregulation was confirmed at the mRNA level and observed with two different siRNAs targeting Cdc42. Such a regulation was also observed in various human cell lines and was rescued by re-expressing wild-type Cdc42 encoded by a construct bearing silent mutations impeding its recognition by the siRNA. By contrast, MMP-2 and type-I-collagen expression was not affected by the individual silencing of each Rho GTPase. Cytokine protein array, enzyme-linked immunosorbent assays and reverse-transcription PCR measurements revealed that ablation of Cdc42 induced an overexpression of interleukin 8 and MCP-1. Although these cytokines are known to induce the expression of MMP-1, we showed that they were not involved in the Cdc42-mediated upregulation of MMP-1. Silencing of Cdc42 also induced an increased phosphorylation of ERK1/2 and p38 MAP kinase. The use of chemical inhibitors on Cdc42-ablated cells revealed that the upregulation of MMP-1 is dependent on the ERK1/2 pathways, whereas the p38 MAP kinase pathway displayed an inhibitory role. Simultaneous knock-down of two or three Rho GTPases allowed us to demonstrate that the RhoA-ROCK pathway was not involved in this regulation but that the silencing of Rac1 reduced the effect of Cdc42 suppression. These data suggest that, in vivo, when cell/extracellular-matrix interactions via integrins induce cytoskeleton organization, MMP-1 expression is maintained at a low level by Cdc42 via a repression of the Rac1 and ERK1/2 pathways. Therefore, Cdc42 contributes to ECM homeostasis and connective tissue integrity.
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PMID:Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway. 1572 53

Immune system dysfunction in the perioperative period, with its combined pro-inflammatory and immuno-suppressive effects, can influence long term disease progression, morbidity, and mortality. Literature on postoperative immune response in schistosomiasis patients is scarce. The aim of this study was to assess the impact of isoflurane anesthesia on pro- and anti-inflammatory cytokine balance in schistosomal patients undergoing minor procedures. The study was conducted on 24 patients (ASA class I-II) scheduled for elective urologic endoscopic procedures. Patients were divided into two groups 12 patients each: control group (n=12) and patient group (n=12). Anaesthesia was induced by a bolus dose of sufentanil 0.2 microg x kg(-1), thiopentone sodium 5 mg x kg(-1), vecuronium 0.1 mg x kg(-1) and maintained by isoflurane 1-1.5 MAC with additional sufentanil bolus of 0.15 microg x kg(-1) when indicated. Venous blood samples were obtained from each patient: before induction, fifteen minutes, one hr after induction and 24 hrs after surgery. Plasma levels of IL-1beta, TNF-alpha, IL-8, IFN-gamma, IL-1ra and TNF-BP1, as well as stress hormones (cortisol and prolactin) were measured. As for pro- and anti-inflammatory cytokine balance, the overall end-result was a rise at 24 hr postoperatively, in the level of TNF-alpha (a key pro-inflammatory cytokine) and IFN-gamma, as well as both anti-inflammatory cytokines (IL-Ira & sTNF-R1). The anti-inflammatory response was more conspicuous in the patients than controls.
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PMID:Does isoflurane anesthesia alter immuno-modulatory response in schistosomal patients? Assessment of serum pro- and anti-inflammatory cytokine balance. 1692 76


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