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)

LIGHT (TNFSF 14) belongs to the tumor necrosis factor super-family and is expressed by different types of immune cells. Recently, LIGHT was found to be associated with platelets and released upon activation. Activation of endothelial cells by recombinant LIGHT results in pro-inflammatory and pro-thrombotic changes, qualitatively comparable to effects of CD40 ligand. Given the important role of platelet-associated CD40 ligand in vascular inflammatory responses we investigated the role of LIGHT for activation of endothelium and adhesion of platelets to endothelial cells. Expression of LIGHT was detected on thrombocytes upon exposure to ADP or TRAP-1. The expression of the LIGHT receptors TR2 and LTbetaR on native human endothelial cells was confirmed by FACS analysis. LIGHT mediated adhesion of platelets to endothelium significantly, occurring both under static and dynamic flow conditions. This interaction was inhibited by a monoclonal antibody to LIGHT but not a control IgG. Moreover, in-vitro stimulation of endothelial cells with recombinant soluble human LIGHT (rhLIGHT) resulted in significantly increased transcriptional and translational upregulation of inflammatory markers ICAM-1, tissue factor (TF) and IL-8. This activation of endothelial cells by LIGHT was mediated by NFkappaB activation and qualitatively comparable to that induced by membrane-bound CD40-ligand on transfected cells. Furthermore, plasma levels of patients with myocardial infarction, in those with ST-elevation myocardial infarction (STEMI), showed increased plasma levels of LIGHT compared with healthy controls. In conclusion, platelet-associated LIGHT is involved in adhesion of platelets to endothelium while soluble LIGHT induces a pro-inflammatory state in vascular endothelial cells. LIGHT may thus be implicated in the pathogenesis of atherosclerosis and acute coronary syndrome, as evidenced by serum levels.
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PMID:Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium. 1793 4

During the last decade, the role of inflammation in the etiopathogenesis of arterial thrombosis has been elucidated. However, little is known about the relationship between inflammation and venous thrombosis. Recently, inflammation has been accepted as a possible mechanism through which different risk factors trigger thrombus formation in veins. The data indicate that inflammation of the vessel wall initiates thrombus formation in an intact vein and that inflammation and coagulation systems are coupled by a common activation pathway. The first event in thrombus formation is most probably activation of endothelial cells, platelets and leucocytes, with initiation of inflammation and formation of microparticles that trigger the coagulation system through the induction of a tissue factor. Therefore, the key event in the initiation of venous thrombus formation is most probably vein wall inflammation. However, expected relationship between inflammatory markers as indicators of inflammatory process and clinical venous thromboembolism (VTE) has not yet been elucidated. C-reactive protein does not appear to be useful in predicting future venous thrombosis or to be useful in the diagnosis of VTE. Recently, it was demonstrated that probable association between VTE and several other markers of inflammation such as: interleukin (IL)-6, IL-8 and tumor necrosis factor-a exists. While these markers of inflammation were studied during or after acute venous thrombosis, further prospective studies are needed to determine the predictive value of inflammatory markers for VTE. The identification and elucidation of inflammatory markers relevant to venous thrombosis could provide targets for future therapy. That inflammation is the basic etiopathogenetic process of VTE is also supported by the relation of some risk factors to both arterial and venous thrombosis: age, increased body mass index, hypercholesterolemia, hypertension, lupus anticoagulant and hyperhomocysteinemia. A relation was also found between preclinical and clinical atherosclerotic disease and VTE. Also in line with these arguments are the preventive effects of aspirin and statins in both arterial and venous disease.
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PMID:The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. 1809 97

Factors that upregulate the inflammatory status of islets probably contribute to detrimental processes leading to islet loss and impaired post-transplant function. Glucocorticoids have the potential to counteract inflammation and thus improve islet quality and function. However, glucocorticoids have diabetogenic properties and are known to hamper islet function in vivo. We examined the effect of glucocorticoids on human islets in vitro and in vivo after 48 h of exposure to different concentrations of methylprednisolone. Protein and/or mRNA levels of insulin, interleukin (IL)-8, macrophage chemoattractant protein (MCP)-1, tissue factor (TF), and IL-10 were assessed by enzyme immunosorbent assay and real time quantitative reverse transcription-polymerase chain reaction. Viability was assessed with fluorescein diacetate-propidium iodide staining, adenosine triphosphate (ATP) content and caspase activity. Six-hundred islet equivalents (IEQ) were transplanted to severe combined immunodeficiency disease mice and graft function assessed by glucose measurements and intraperitoneal glucose tolerance tests. Glucocorticoids reduce mRNA and protein levels of TF, MCP-1 and IL-8, and enhance ATP content. Insulin secretion was initially inhibited; however, after 7 days in culture, it was superior to controls. Islets exposed to methylprednisolone cured diabetic mice more effectively than control islets. In conclusion, glucocorticoids have potent anti-inflammatory properties on human islets without permanent effects on insulin metabolism. Brief glucocorticoid exposure improves function of transplanted human islets in vivo.
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PMID:Glucocorticoids reduce pro-inflammatory cytokines and tissue factor in vitro and improve function of transplanted human islets in vivo. 1834 12

Animal venomous secretions have been explored as source of active substances affecting mammal hemostasis. These active principles impinge on key elements of almost all physiologic pathways and have an enormous potential in the development of new therapeutic drugs. The envenomation caused by the caterpillar Lonomia obliqua (lonomism) is characterized by a hemorrhagic clinical profile. Investigations of caterpillar venom have, in general, involved the isolation and biochemical characterization of active principles related to the pathophysiology of envenomation. In the last few years, these studies focused on the caterpillar's secretions pro-coagulant, fibrin(ogen)olytic, hemolytic, edematogenic and nociceptive activities. Recently, a significant advance was achieved as a result of a transcriptome study, which generated a catalog of putative toxic proteins in the caterpillar venom, giving rise to hypotheses on the molecular basis of pathogenesis which could be experimentally explored. In this investigation, using a microarray methodology, we analyzed the effects of the caterpillar venom on the gene expression profile of cultured human fibroblasts with the aim of gaining insight into genes possibly associated with the clinical manifestations of lonomism. Our hypothesis was that both the direct action L. obliqua venomous proteins on the host as well as an indirect effect caused by alteration in the gene expression pattern in host tissues could function in concert and perhaps synergistically to give rise to the profound symptoms observed during lonomism. Interesting changes in the expression pattern of some genes, such as IL-8, prostaglandin-endoperoxide synthase 2, urokinase-type plasminogen activator receptor and tissue factor, were observed in treated fibroblasts, which could contribute to some of the observed pathological sequela in lonomism. Thus, lonomism appears to be a result of both the previously described direct effects of the venom as well as indirect effects caused by changes in host gene expression profiles. These studies have enhanced our understanding of lonomism and may contribute to insights into more effective treatments.
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PMID:Novel perspectives on the pathogenesis of Lonomia obliqua caterpillar envenomation based on assessment of host response by gene expression analysis. 1836 25

We measured and compared the levels of microparticles, chemokines, cell adhesion molecules and platelet activation markers with a view to developing a better understanding of their potential contributions to the pathophysiology of progressive systemic sclerosis (PSS, scleroderma). The concentrations of all the factors in PSS patients were significantly higher than those in normal subjects. PSS patients were divided to two groups by whether they have interstitial pneumonia (IP) or not. There were no differences in the levels of soluble(s) VCAM-1, sICAM-1, sE-selectin and IL-8 between the two groups. However, there were significant between-group differences in the levels of sP-selectin, sCD40L, ENA-78, RANTES (regulated on activation normally T-cell expressed and secreted), platelet-derived microparticles (PDMPs), monocyte-derived microparticle (MDMPs) and KL-6. The level of tissue factor expression on monocytes by A23187 stimulation in PSS patients was found to be similar to that in healthy controls. Although PDMP did not induce the expression of tissue factor on monocytic cell line (THP-1) directly, the recombinant sCD40 ligand-induced expression of tissue factor on THP-1 and generation of MDMP from this cell line were enhanced by the addition of PDMPs. Our findings suggested that elevated levels of PDMPs and MDMPs may be interpreted as a sign of vascular complications in PSS patients, particularly those complicated with IP, offering a new treatment strategy in these patients.
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PMID:Significance of microparticles in progressive systemic sclerosis with interstitial pneumonia. 1843 20

Dengue fever is the most prevalent viral disease transmitted by vectors (Aedes aegypti, Aedes albopictus) in worldwide. More than 100 million cases occur annually with a mortality rate of 5% and no safe vaccine is available. The pathogenesis of Dengue, where host and viral factors participate in the establishment of Dengue haemorrhagic fever (DHF) and Dengue shock syndrome (DSS) remains unresolved. Clinical observations have revealed significant abnormalities in coagulation and inflammation systems, with increased levels of tissue factor (TF) and the chemokine IL-8, correlating with the severity of the disease and implicating damage to endothelial vascular cells (EVC). Here we present novel insights concerning the crosstalk between the regulatory signaling pathways of the coagulation-inflammation processes, during Dengue virus (DV) infection of EVC. We found that DV up-regulates Protease Activated receptor type-1 (inflammation) and TF (coagulation) receptors, via the phosphorylation of p38 and ERK1/2 MAPKs, which favor the activation of NF-kappaB transcription factor. This induces pro-inflammatory (IL-8) or pro-adhesive (VCAM-1) gene expression which may lead to EVC activation. The elucidation of the basic principles that signal these processes has important implications for the design of new therapeutic strategies for DHF/DSS.
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PMID:Crosstalk between coagulation and inflammation during Dengue virus infection. 1844 25

Tissue factor (TF) is believed to play an important role in tissue repair, inflammation, angiogenesis, and tumor metastasis. Protease-activated receptors (PARs) are widely expressed on various cells including tumor cells and associated with many pathological mechanisms. In the present study, the expression of TF and PAR1, PAR2 on human colon cancer cells (SW620 and SW480) was investigated and their functional roles on the behavior of tumor cells were evaluated. It was demonstrated that SW620 and SW480 cells expressed TF at antigen, activity and mRNA levels. However, the highly metastatic cell line SW620 showed slightly higher TF expression than the low metastatic cell line SW480. The PAR2 antigen was strongly expressed on the membrane of SW620 cells, but not on SW480 cells. The PAR1 antigen was not observed in SW620 or SW480 cells, while PAR1 and PAR2 mRNA was detected in SW620 and SW480 cells. The migratory potential of SW620 was stronger than that of SW480 seen in Boyden chambers. PAR2 agonist (SLIGKV-NH2) and factor VIIa significantly stimulated SW620 cell proliferation, migratory activity, and interleukin 8 (IL-8) secretion compared to control. The stimulating effects of factor VIIa could be inhibited by anti-TF and anti-PAR2 but not anti-PAR1 antibodies. In summary, this study demonstrates that TF and PAR2 are strongly expressed on highly metastatic colonic tumor cells and are closely associated with the proliferation and migration of the cells. TF may elucidate its roles in colonic cancer invasion and metastasis via PAR2 pathway.
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PMID:The expression and the functional roles of tissue factor and protease-activated receptor-2 on SW620 cells. 1894 3

Hyphal invasion of blood vessels is a prominent feature of invasive aspergillosis. During invasive pulmonary aspergillosis, Aspergillus fumigatus hyphae invade the abluminal endothelial cell surface, whereas they invade the luminal endothelial cell surface during haematogenous dissemination. We investigated the endothelial cell response to abluminal and luminal infection with A. fumigatus hyphae in vitro. We found that these hyphae invaded the abluminal endothelial cell surface without inducing the formation of endothelial cell pseudopods. Also, the internalized hyphae were surrounded by a loose network of microfilaments. In contrast, A. fumigatus hyphae invaded the luminal endothelial cell surface by inducing by the formation of endothelial cell pseudopods. These endocytosed hyphae were surrounded by a tight network of microfilaments. Abluminal infection induced greater E-selectin, IL-8, tissue factor and TNF-alpha gene expression, but less endothelial cell damage than did luminal infection. Endothelial cell stimulation by infection of either surface was mediated by endothelial cell-derived TNF-alpha, and was not influenced by gliotoxin secreted by A. fumigatus. These differences in the endothelial cell response to abluminal versus luminal infection may contribute to differences in the pathogenesis of invasive versus haematogenously disseminated aspergillosis.
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PMID:Polarized response of endothelial cells to invasion by Aspergillus fumigatus. 1901 88

The Staphylococcus aureus fibronectin (Fn) -binding protein A (FnBPA) is involved in bacterium-endothelium interactions which is one of the crucial events leading to infective endocarditis (IE). We previously showed that the sole expression of S. aureus FnBPA was sufficient to confer to non-invasive Lactococcus lactis bacteria the capacity to invade human endothelial cells (ECs) and to launch the typical endothelial proinflammatory and procoagulant responses that characterize IE. In the present study we further questioned whether these bacterium-EC interactions could be reproduced by single or combined FnBPA sub-domains (A, B, C or D) using a large library of truncated FnBPA constructs expressed in L. lactis. Significant invasion of cultured ECs was found for L. lactis expressing the FnBPA subdomains CD (aa 604-877) or A4(+16) (aa 432-559). Moreover, this correlates with the capacity of these fragments to elicit in vitro a marked increase in EC surface expression of both ICAM-1 and VCAM-1 and secretion of the CXCL8 chemokine and finally to induce a tissue factor-dependent endothelial coagulation response. We thus conclude that (sub)domains of the staphylococcal FnBPA molecule that express Fn-binding modules, alone or in combination, are sufficient to evoke an endothelial proinflammatory as well as a procoagulant response and thus account for IE severity.
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PMID:Contribution of (sub)domains of Staphylococcus aureus fibronectin-binding protein to the proinflammatory and procoagulant response of human vascular endothelial cells. 1927 11

Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.
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PMID:Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature. 1971 55


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