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)

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.
 ...
PMID:Thrombin receptor expression and responsiveness of human monocytic cells to thrombin is linked to interferon-induced cellular differentiation. 973 47

Oxidative stress and systemic inflammation in chronic obstructive pulmonary disease (COPD) strongly suggest a role for the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1, E.C.2.4.2.30) in the disease pathophysiology. PARP-1 is highly activated by reactive oxygen species-induced DNA strand breaks, upon which it forms extensive poly(ADP-ribose) (PAR) polymers from its substrate NAD(+). We hypothesized that in COPD, chronic inflammation and oxidative stress would lead to systemic PARP-1 activation and to a reduced NAD(+) status. In a patient-control study, systemic PARP-1 activation was assessed by immunofluorescent detection of PAR polymers in peripheral blood lymphocytes. The percentage of PAR polymer-positive lymphocytes appeared to be higher in COPD patients (27 +/- 3%) than in healthy age-matched controls (17 +/- 2%, p <.05). Trolox equivalent antioxidant capacity (TEAC) of deproteinized plasma (p <.001), plasma uric acid (p <.05), as well as blood NAD(+) (p <.01) of stable COPD patients were significantly reduced when compared to controls. In addition, levels of proinflammatory cytokines IL-6, IL-8, and sICAM-1 were increased (p <.005) in COPD patients. In this study, evidence was found for the presence of systemic inflammation, chronic oxidative stress, and systemic PARP-1 activation in stable COPD patients. These data support a contribution of oxidative stress-induced PARP-1 activation to the pathophysiology of COPD.
 ...
PMID:Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients. 1285 70

The presence of thrombin and its receptor, protease-activated receptor 1 (PAR 1), in the ovary suggests that thrombin may regulate ovarian function. In particular, to address the possible role of thrombin in ovulation, a phenomenon displaying mimicry of inflammation, we investigated the effects of thrombin and PAR 1 on the production of inflammation-related substances in human luteinized granulosa cells (LGC). Thrombin stimulated the production of IL-8 and monocyte chemoattractant protein-1 by cultured LGC. The stimulatory effects of thrombin were inhibited by both inhibitors of thrombin (hirudin and PPACK) and a protein kinase C inhibitor (calphostin C). The PAR 1 agonist, SFLLRN, also stimulated the production of IL-8 and monocyte chemoattractant protein-1. Thrombin and SFLLRN stimulated the geletinase activities of LGC, the effect of both being inhibited by hirudin and PPACK. Immunocytochemical study showed that thrombin and SFLLRN induced translocation of nuclear factor kappaB to the nucleus from the cytoplasm in LGC. Expression of PAR 1 mRNA was detected in LGC by RT-PCR analysis. These findings suggest that thrombin plays physiological roles in ovulation by enhancing the production of chemoattractive and gelatinolytic substances by granulosa cells by a mechanism involving PAR 1.
 ...
PMID:Possible roles of thrombin-induced activation of protease-activated receptor 1 in human luteinized granulosa cells. 1291 92

Protease-activated receptor-2 (PAR-2) belongs to a family of G-coupled receptors activated by proteolytic cleavage to reveal a tethered ligand. PAR-2 is activated by trypsin and trypsin-like serine proteases and experimentally, by receptor-activating peptides (APs), which mimic the tethered ligand. PAR-2 has recently been implicated in proinflammatory immune responses. For example, PAR-2(-/-) mice exhibit markedly diminished contact hypersensitivity reactions and are completely resistant to adjuvant-induced arthritis. The present study shows that human blood monocytes express low-level cell-surface PAR-2 ex vivo, which is up-regulated upon cell purification by the mobilization of intracellular stores of PAR-2 protein. PAR-2 expression is also present on monocyte-derived macrophages, but only a small proportion of monocyte-derived dendritic cells (DC) is PAR-2(+), and blood DC are PAR(-). Freshly isolated monocytes responded to the PAR-2 AP ASKH 95 (2-furoyl-LIGKV-OH) with the generation of a calcium flux and production of interleukin (IL)-1beta, IL-6, and IL-8. The results presented thus suggest that PAR-2 contributes to inflammatory responses by inducing the production of proinflammatory cytokines in peripheral blood monocytes.
 ...
PMID:Human peripheral blood monocytes express protease receptor-2 and respond to receptor activation by production of IL-6, IL-8, and IL-1{beta}. 1600 Mar 89

We investigated and compared the mechanisms by which two dust mite proteolytic allergens, Der p 1 and Der p 3, and a peptide agonist of proteinase-activated receptor 2 (PAR(2)AP) trigger interleukin (IL)-8 release from human pulmonary epithelial cells (A549). Although all three stimuli tested induced the up-regulation of IL-8 (mRNA and protein), the Der p 1-mediated signaling events did not exactly match those induced by PAR(2)AP and Der p 3. First, Der p 1 was less effective in stimulating IL-8 gene transcriptional activity than PAR(2)AP and Der p 3. Second, Der p 1-mediated IL-8 expression was mainly dependent on NF-kappaB, whereas Der p 3 and PAR(2)AP regulated IL-8 expression through the activation of both NF-kappaB and AP-1. Third, although all three MAP kinases, ERK1/2, p38, and JNK, were activated, Der p 1 induced IL-8 release exclusively via the ERK1/2 signaling pathway, whereas PAR(2)AP and Der p 3 also involved the other kinases. Fourth, in HeLa cells, Der p 1 was able to up-regulate IL-8 secretion independent of PAR(2) expression, and in contrast with PAR(2)AP and Der p 3, Der p 1 was unable to affect calcium signaling via PAR(2) in PAR(2)-expressing KNRK cells. Finally, cleavage by Der p 1 of a synthetic peptide representing the N-terminal activation-cleavage site of PAR(2) did not release a high potency activator of PAR(2) as does Der p 3. We conclude that Der p 1 (but not Der p 3)-induced IL-8 production in A549 epithelial cells is independent of PAR(2) activation.
 ...
PMID:The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism. 1629 28

Clostridium difficile-associated disease (CDAD) has become an important public health problem. The causative organism is acquired by the oral route from an environmental source or by contact with an infected person or a health care worker who serves as a vector. Disruption of the bowel microflora, generally by antibiotics, creates an environment that allows C. difficile to proliferate. Organisms produce toxins A and B, which cause intense inflammation of the colonic mucosa. The syndrome that results includes severe diarrhea, fever, abdominal pain, and leukocytosis. A new strain of C. difficile has become prevalent in the United States, Canada, and the United Kingdom. Identified by pulsed-field gel electrophoresis (PFGE), this strain is called North America PFGE type 1, abbreviated as NAP-1. Clostridium difficile NAP-1 characteristically generates large amounts of toxins A and B, as well as an additional binary toxin and is associated with enhanced morbidity and a poor response to antibiotic therapy. Mild cases of CDAD may respond to cessation of antibiotic therapy, perhaps related to antibody production by the infected person, but most infected persons require antimicrobial therapy. Vancomycin has been approved by the United States Food and Drug Administration for treatment of CDAD, but reluctance to use this antibiotic in the hospital setting has led to reliance on metronidazole as first-line therapy. Recent studies show a high rate of failure, due either to infection by NAP-1 or to the presence, in hospitals, of older and sicker adults who have been treated with many broad-spectrum antibiotics. Nitazoxanide, bacitracin, teicoplanin, and fusidic acid are additional agents that have published efficacy for this indication in humans. Rifaximin and PAR-101 are under investigation. Other therapies, including polymers that bind C. difficile toxin and monoclonal antibodies to toxins, and preventive measures such as toxoid vaccines are also under study.
 ...
PMID:Clostridium difficile: recent epidemiologic findings and advances in therapy. 1759 9

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRR) and transduces downstream signaling to activate the host defense. Here we report that in addition to direct PAMP-PRR interactions, live Candida albicans cells can release soluble factors to actively potentiate interleukin-6 (IL-6) and IL-8 production induced in human mononuclear cells by the fungi. Although protease-activated receptor 1 (PAR1) and PAR2 ligation can moderately upregulate Toll-like receptor 4 (TLR4)-mediated IL-8 production, no effect on the C. albicans-induced cytokine was apparent. Similarly, the blockade of PAR signaling did not reverse the potentiation of cytokine production induced by soluble factors released by C. albicans. In conclusion, C. albicans releases soluble factors that potentiate cytokine release in a PAR1/2-independent manner. Thus, human PAR1 and PAR2 have a redundant role in the activation of human cells by C. albicans.
 ...
PMID:Candida albicans releases soluble factors that potentiate cytokine production by human cells through a protease-activated receptor 1- and 2-independent pathway. 1985 10

Expression of PAR, the thrombin receptor, is elevated in smooth muscle cell-rich areas in atherosclerotic plaques, where the cells change to proinflammatory or synthetic phenotype. In this study we investigated whether thrombin promotes a proinflammatory phenotype in vascular smooth muscle cell (VSMC), characterized by increased cytokine and chemokine synthesis. Thrombin not only elevated transcripts for IL-6, CXCL8, and CCL11 genes but also enhanced release of IL-6 and CXCL8 protein from human aortic smooth muscle cell (HAoSMC). Thrombin activated Akt, PKC and MAPK in HAoSMC, and thrombin-mediated expression of IL-6 and CXCL8 was significantly inhibited by LY294002, AKT IV, RO318220, and GF109203X as well as by diphenyleneiodium at the messenger RNA and the protein levels. SB202129 and U0126 also significantly attenuated thrombin-mediated release of IL-6 and CXCL8 proteins from HAoSMC. These results indicate that thrombin promotes proinflammatory phenotype in human VSMC and that PI3K, Akt, PKC, NADPH oxidase, and MAPK are involved in that process. We propose that activation VSMC in response to thrombin after endothelial injury and/or thrombus formation will enhance inflammation in vasculature.
 ...
PMID:Thrombin promotes proinflammatory phenotype in human vascular smooth muscle cell. 2045 99

No evidence for the role of protease-activated receptor-2 (PAR(2)) in human periodontal disease has been demonstrated so far. Thus, we sought to investigate the expression of PAR(2) mRNA in chronic periodontitis, and to examine whether its expression is related to the presence of PAR(2) potential activators. Microbiological and gingival crevicular fluid samples were collected from individuals with chronic periodontitis and control individuals, and the presence of neutrophil serine proteinase 3 (P3) and Porphyromonas gingivalis was evaluated. PAR(2) mRNA expression was higher (p < 0.001) in those with chronic periodontitis compared with control individuals, and it was statistically decreased (p = 0.0006) after periodontal treatment. Furthermore, those with chronic periodontitis presented higher (p < 0.05) levels of IL-1alpha, IL-6, IL-8, and TNF-alpha, total proteolytic activity, P. gingivalis prevalence, and P3mRNA expression compared with control individuals. We conclude that PAR(2) mRNA expression and its potential activators are elevated in human chronic periodontitis, therefore suggesting that PAR(2) may play a role in periodontal inflammation.
 ...
PMID:Protease-activated receptor-2 (PAR(2)) in human periodontitis. 2053 Jul 26

Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we hypothesized that GrK induces pro-inflammatory cytokine release through the activation of protease-activated receptors. The direct effect of extracellular GrK on PAR activation, intracellular signaling and cytokine was assessed using cultured human lung fibroblasts. Extracellular GrK induced secretion of IL-6, IL-8 and MCP-1 in a dose- and time-dependent manner in lung fibroblasts. Heat-inactivated GrK did not induce cytokine release indicating that protease activity is required. Furthermore, GrK induced activation of both the ERK1/2 and p38 MAP kinase signaling pathways, and significantly increased fibroblast proliferation. Inhibition of ERK1/2 abrogated the GrK-mediated cytokine release. Through the use of PAR-1 and PAR-2 neutralizing antibodies, it was determined that PAR-1 is essential for GrK-induced IL-6, IL-8 and MCP-1 release. In summary, extracellular GrK is capable of activating PAR-1 and inducing fibroblast cytokine secretion and proliferation.
 ...
PMID:Granzyme K activates protease-activated receptor-1. 2176 Aug 80


1 2 Next >>