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)

Since Epstein-Barr virus (EBV) infection of Burkitt's lymphoma (BL) cells in vitro reproduces many of the activation effects of EBV infection of primary B lymphocytes, mRNAs induced in BL cells have been cloned and identified by subtractive hybridization. Nine genes encode RNAs which are 4- to > 100-fold more abundant after EBV infection. Two of these, the genes for CD21 and vimentin, were previously known to be induced by EBV infection. Five others, the genes for cathepsin H, annexin VI (p68), serglycin proteoglycan core protein, CD44, and the myristylated alanine-rich protein kinase C substrate (MARCKS), are genes which were not previously known to be induced by EBV infection. Two novel genes, EBV-induced genes 1 and 2 (EBI 1 and EBI 2, respectively) can be predicted from their cDNA sequences to encode G protein-coupled peptide receptors. EBI 1 is expressed exclusively in B- and T-lymphocyte cell lines and in lymphoid tissues and is highly homologous to the interleukin 8 receptors. EBI 2 is most closely related to the thrombin receptor. EBI 2 is expressed in B-lymphocyte cell lines and in lymphoid tissues but not in T-lymphocyte cell lines or peripheral blood T lymphocytes. EBI 2 is also expressed at lower levels in a promyelocytic and a histiocytic cell line and in pulmonary tissue. These predicted G protein-coupled peptide receptors are more likely to be mediators of EBV effects on B lymphocytes or of normal lymphocyte functions than are genes previously known to be up-regulated by EBV infection.
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PMID:Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. 838 38

Interleukin-8 (IL-8) is regarded as an important mediator of inflammation because of its potent and specific chemotactic activity on neutrophils. In the present investigation, human umbilical vein endothelial cells (HUVEC) stimulated with thrombin were found to produce IL-8, in a dose- and time-dependent manner. After stimulation with 10 U/ml thrombin for 24 hr, the level of IL-8 in the conditioned medium was 14 ng/ml, or enough to elicit PMN chemotaxis in vitro. Northern blot analysis revealed that thrombin as well as IL-1 beta elevates the level of IL-8 mRNA preceding the formation of IL-8 protein. A synthetic peptide SFLLRN [human thrombin receptor-activating peptide (TRAP)] was found to mimic the action of thrombin. Preincubation with anti-thrombin compounds such as hirudin and antithrombin-III-heparin almost completely suppressed the action of thrombin without affecting the actions of other stimuli including IL-1 beta, phorbol 12-myristate 13-acetate (PMA) and TRAP. Diisopropylfluorophosphate-treated thrombin did not stimulate IL-8 production. Calphostin-C, a protein kinase C (PKC) inhibitor, attenuated the production of IL-8 by thrombin, TRAP and PMA, but left the action of IL-1 beta unchanged. These results strongly suggest that catalytic activation of thrombin receptor by thrombin results in PKC-dependent IL-8 production accompanied by an increase in IL-8 mRNA level.
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PMID:Thrombin stimulates production of interleukin-8 in human umbilical vein endothelial cells. 870 54

Granzymes, serine proteases located in the granules of cytotoxic T cel ls and NK cells, are essential for induction of target cell apoptosis. However, since cytotoxic cells constitutively secrete a portion of their synthesized granzymes, these proteases could mediate extracellular functions independent of their role in the lytic event. Thrombin, another serine protease, can induce cytokine production in a number of different cell types. In this study, we test the hypothesis that granzymes, like thrombin, can regulate cell-mediated immunity by inducing the production of different cytokines. We show that granzyme A (GA) stimulates IL-6, IL-8, and TNF-alpha production by human PBMC and purified monocytes. In contrast, monocytes exposed to thrombin had enhanced IL-8 production with no induction of IL-6 or TNF-alpha production. However, monocytes exposed to either GA or thrombin had enhanced phagocytic activity. The enzymatic activity of GA and thrombin was required for the induction of cytokine production and for the enhancement of phagocytic activity. The induction of different cytokine profiles by GA vs thrombin suggested that GA activates monocytes via a receptor that was different from the thrombin receptor. This conclusion was strengthened by the fact that GA was incapable of inducing Ca2+ mobilization in insect cells transfected with the thrombin receptor. These results suggest that enzymatically active GA mediates important immunoregulatory functions through signaling pathways that does not involve thrombin receptor activation.
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PMID:Extracellular activities of human granzyme A. Monocyte activation by granzyme A versus alpha-thrombin. 878 23

We studied the effects of serine proteases on cytokine gene expression by cultured normal human keratinocytes. In resting keratinocytes, steady-state mRNA levels for interleukins IL-1 alpha, IL-1 beta, IL-7, and IL-8, transforming growth factors alpha and beta, and tumor necrosis alpha were sufficient to be detected by our reverse transcriptase-polymerase clozin reaction method. Incubation of keratinocytes with 25 nM trypsin or 1 unit/ml thrombin for 24 hr selectively upregulated mRNA levels for granulocyte-macrophage colony-stimulating factor (GM-CSF) and Il-6 to detectable levels. Keratinocytes secreted GM-CSF and IL-6 protein in response to these proteases. Monensin did not inhibit the gene expression for the cytokines, thereby excluding the possibility of intervention by secreted molecules. Aprotinin and argatroban inhibited the effects of the proteases. SFLLRN and SLIGRL, tethered ligand receptor peptides for thrombin receptor and for proteinase-activated receptor 2 (PAR-2), respectively, duplicated the effects of the proteases on keratinocytes, which expressed mRNA for both receptors. Trypsin increased tyrosine phosphorylated proteins and intracellular free calcium concentrations. Tyrphostin, pertussis toxin, or H-7 suppressed trypsin- and thrombin-induced GM-CSF gene expression. Our results demonstrate that the serine proteases activate thrombin receptors and PAR-2 on keratinocytes, triggering intracellular signaling and then inducing the synthesis of GM-CSF. We speculate that serine proteases modulate the course of physiological and pathological processes in the skin by stimulating keratinocytes to produce the cytokines.
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PMID:Thrombin and trypsin induce granulocyte-macrophage colony-stimulating factor and interleukin-6 gene expression in cultured normal human keratinocytes. 906 88

In addition to its role in coagulation, thrombin is involved in the inflammatory process by inducing vessel neutrophilic infiltration. Thrombin induces endothelial P-selectin expression and platelet activating factor release, which participate to induce early neutrophil adhesion and activation. We employed HUVEC and now show that thrombin induces the production of the chemokine IL-8 in a time- and dose-dependent fashion. Similarly, thrombin induced E-selectin expression on HUVEC. Both IL-8 secretion and E-selectin expression were preceded by an increase in steady state levels of the respective mRNAs. Thrombin action on HUVEC was inhibited by the specific thrombin inhibitor, hirudin. In addition, these effects of thrombin on HUVEC were mimicked by the 14-amino acid thrombin receptor agonist peptide, which triggers the native thrombin receptor in a similar fashion to thrombin itself. Although IL-1 and TNF-alpha also induce IL-8 and E-selectin, the thrombin effects in these experiments were not mediated by those cytokines, since neither IL-1 receptor antagonist nor anti-TNF-alpha Ab inhibited the effects of thrombin. Furthermore, IL-1alpha, IL-1beta, and TNF-alpha were not detected in the supernatants of thrombin-activated HUVEC. Although intracellular IL-1alpha was found in thrombin-activated HUVEC, antisense IL-1alpha had no inhibitory effect on IL-8 secretion. These results demonstrate that in addition to short term endothelial activation, thrombin also functions as a long acting proinflammatory agent by inducing endothelial synthesis of the mediators required for neutrophils activation and extravazation during inflammation.
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PMID:Thrombin induces endothelial type II activation in vitro: IL-1 and TNF-alpha-independent IL-8 secretion and E-selectin expression. 916 65

Thrombin is the central bioregulatory enzyme in hemostasis and is generated in vascular beds in which inflammatory responses are ongoing. In this study, we examined the effect of thrombin, both alone and in combination with TNF, on gene expression in porcine aortic endothelial cells (EC). Thrombin (1-10 U/ml) induced increased mRNA levels of E-selectin, monocyte chemoattractant protein-1, IL-8, plasminogen activator inhibitor-1, and IkappaB-alpha. These effects were mimicked by a thrombin receptor-activating peptide; preincubation of thrombin with hirudin blocked the induction of mRNA, suggesting that the increased gene expression was due to thrombin-specific activity. Because these genes are known to contain nuclear-factor-kappaB (NF-kappaB)-binding elements in their promoter region, we next examined the ability of thrombin to activate this transcription factor. As detected by electrophoretic mobility shift assay, thrombin (10 U/ml) or thrombin receptor-activating peptide (100 microM) stimulated increased NF-kappaB-binding activity. Supershift analysis revealed that these complexes were comprised principally of the RelA (p65) and NF-kappaB1 (p50) Rel family members. Thrombin alone did not substantively increase protein levels of E-selectin despite the increase in E-selectin mRNA levels. However, thrombin (3-10 U/ml) stimulated a 10-fold enhancement in the ability of TNF (0.3-1.0 ng/ml) to induce E-selectin surface expression. Similar potentiation of TNF-induced NF-kappaB activity and E-selectin transcription by thrombin was observed in experiments utilizing luciferase reporter constructs expressed in bovine aortic EC. The ability of thrombin to potentiate TNF-induced EC activation thus provides an important mechanism by which products of the coagulation cascade may enhance cytokine-mediated inflammatory responses.
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PMID:Thrombin activates nuclear factor-kappaB and potentiates endothelial cell activation by TNF. 954 5

We have previously shown that an anticoagulant could attenuate inflammation in animal models of sepsis with disseminated intravascular coagulation (DIC) and that coagulation activation of human whole blood ex vivo results in a proinflammatory cytokine response. The current studies were performed to better understand mechanisms for the blood cell cytokine response and extend the investigation of such a response to endothelial cells as likely contributors to a vascular inflammatory response. Utilizing cell separation techniques, it was determined that the whole blood IL-8 response to coagulation activation or thrombin, specifically, was mediated by CD14+ monocytes. Moreover, thrombin was observed to stimulate both IL-8 and IL-6 production in cultured mononuclear cells. Analyses of the effects of coagulation activation and thrombin were extended to cultured human endothelial cells, and a similar cytokine response was observed. Thrombin catalytic activity appeared essential, since hirudin reduced thrombin-stimulated proinflammatory cytokine production in cultured monocytes and endothelial cells and prothrombin only weakly mimicked the thrombin response. The endothelial cell IL-8 and IL-6 response to thrombin could be mimicked by the thrombin receptor agonist peptide (TRAP), implicating a functional role of the classic thrombin receptor. Altogether, the results facilitate a better understanding of potential proinflammatory vascular responses to coagulation activation.
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PMID:Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. 959 Feb 65

Human thrombin has been shown to stimulate monocyte chemotaxis, phagocytosis, and interleukin (IL8) production, but the mechanisms responsible for stimulation are not well defined. In some cells, thrombin stimulation of proliferation appears to require both cleavage of the proteolytically activated receptor for thrombin (PAR1) and activation of a nonproteolytically activated thrombin receptor (N-PAR), while in others activation of either receptor alone may be sufficient for stimulation. We, therefore, have initiated studies to address thrombin receptor expression and cell responsiveness to thrombin in interferon gamma (IFNgamma)-differentiated and nondifferentiated U937 monocytic cells. Northern blot analysis shows that PAR1 expression is upregulated upon differentiation. Experiments with biotinylated and 125I-thrombin show that specific thrombin binding is dramatically increased by differentiation although it is not clear if this binding is to PAR1 or to a separate binding component such as N-PAR which is present on fibroblasts and other cells. Addition of thrombin at concentrations of 1-10 microg/ml (30-300 nM, concentrations where specific thrombin binding is observed) stimulates proliferation of IFNgamma-differentiated U937 cells but not of undifferentiated U937 cells. Thrombin also stimulates interleukin-6 (IL6) production in IFNgamma-differentiated U937 cells. Moreover, thrombin induces high levels of IL6, interleukin-1beta (IL1beta), and tumor necrosis factor-alpha (TNF alpha) production by peripheral blood mononuclear cells (PBMC) and monocytes. These results show that differentiated U937 cells and mature PBMC are responsive to thrombin whereas nondifferentiated U937 are not. Further, this responsiveness appears to correlate with expression of PAR1 and to a dramatic increase in specific thrombin binding. That thrombin stimulates cytokine production and proliferation in populations of differentiated monocytes suggests that thrombin may be an important regulator of inflammation and wound healing.
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PMID:Thrombin receptor expression and responsiveness of human monocytic cells to thrombin is linked to interferon-induced cellular differentiation. 973 47

Blood coagulation and inflammation pathways are linked in many aspects. A number of serum factors involved in coagulation cascades affect directly or indirectly inflammatory responses, whereas proinflammatory cytokines influence blood coagulation pathways. In this work we demonstrated that thrombin is an effective stimulus in inducing interleukin (IL)-8 expression in human monocytic cell line U937. IL-8 induction was found at the mRNA and protein levels. The effect of thrombin on IL-8 production was mimicked by thrombin receptor-activating peptide indicating that thrombin effect was mediated by the specific receptor for thrombin. Moreover, thrombin-induced IL-8 production by U937 cells was differentially regulated by interferon (IFN)-gamma and prostaglandin (PG)E2. While IFN-gamma enhanced thrombin-induced IL-8 production, PGE2 acted as a negative regulator. Taken together, thrombin may play an important role in communication between blood coagulation and inflammation by inducing IL-8 production by monocytes and this role for thrombin may be further regulated by lymphokines and lipid mediators.
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PMID:Thrombin-induced interleukin-8 production and its regulation by interferon-gamma and prostaglandin E2 in human monocytic U937 cells. 1036 30

Acute and chronic interstitial lung diseases are accompanied by evidence of inflammation and vascular injury. Thrombin activity in bronchoalveolar lavage fluid from such conditions is often increased, as well as interleukin (IL)-8. We observed that conditioned medium from lung fibroblasts exposed to thrombin has chemotactic activity for polymorphonuclear cells, and that this activity can be abolished by antibody to IL-8. We report that thrombin stimulates expression of IL-8 in human lung fibroblasts on both the messenger RNA and protein levels in a time- and dose-dependent manner. Stimulation of IL-8 expression by thrombin is inhibited by specific thrombin inhibitors. Synthetic thrombin receptor agonist peptide-14 mimics thrombin's stimulation of IL-8 expression in a dose-dependent manner consistent with the idea that upregulation of IL-8 by thrombin in human lung fibroblasts requires cleavage of proteolytically activated receptor-I. We demonstrate further that thrombin-induced IL-8 synthesis is regulated by protein kinase (PK) C. PKC-gamma may be involved in the upregulation of lung fibroblast IL-8 by thrombin because stimulation of lung fibroblasts with thrombin caused significant upregulation of PKC-gamma and because PKC-gamma antisense oligonucleotides inhibited the accumulation of PKC-gamma protein and IL-8 protein. Our data suggest that the PKC-gamma isoform increase observed after thrombin stimulation is required for thrombin-induced IL-8 formation by human lung fibroblasts.
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PMID:Thrombin upregulates interleukin-8 in lung fibroblasts via cleavage of proteolytically activated receptor-I and protein kinase C-gamma activation. 1065 45


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