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)

The administration of a high-dose of a serine protease inhibitor is recommended in patients complicated by multiple organ failure (MOF), including adult respiratory distress syndrome (ARDS), induced by acute pancreatitis. The accumulation of polymorphonuclear leukocytes (PMN) in affected organs is considered to be one of the causative factors of MOF. Adhesion to endothelial cells (EC), via adhesion molecules, and the transendothelial migration of PMN is closely associated with the accumulation of PMN. We examined the effects of two serine protease inhibitors, ulinastatin (UT) and gabexate mesilate (GM), on EC-PMN adhesion and transendothelial migration in human umbilical vein EC and 51Cr-labeled PMN in vitro. EC-PMN adhesion, and the expression of intercellular adhesion molecule-1 (ICAM-1) and endothelial cell adhesion molecule-1 (ELAM-1) on EC induced by IL-1 beta and TNF alpha, were reduced by the pretreatment of EC with these inhibitors. The transendothelial migration of PMN stimulated by IL-8 was also inhibited by pretreating PMN with UT or GM. We also examined whether these inhibitors reduced PMN accumulation in the lung in rats with acute pancreatitis induced by a closed duodenal loop. The myeloperoxidase activity in and histological findings of the lung suggested that UT and GM reduced PMN accumulation. In conclusion, serine protease inhibitors may inhibit PMN accumulation in ARDS due to acute pancreatitis.
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PMID:Effects of serine protease inhibitors on accumulation of polymorphonuclear leukocytes in the lung induced by acute pancreatitis in rats. 764 5

The connective tissue-activating peptide III (CTAP-III), which is released from activated platelets, represents an inactive precursor of the chemokine neutrophil-activating peptide 2 (NAP-2). Leukocytes and leukocyte-derived proteases have been found to convert CTAP-III into NAP-2 by proteolytic cleavage at the N terminus. We demonstrate here that rapid and efficient formation of NAP-2 is mediated by neutrophil granulocytes (PMN) but not by monocytes or lymphocytes. However, as seen in a degranulation assay, neutrophils processing CTAP-III did not become activated by the generated NAP-2 and even exhibited decreased responsiveness to high doses of NAP-2 or IL-8, but not to FMLP. The desensitizing effect, being maximal already after 5 min of preincubation with CTAP-III, was not mediated through binding of the precursor to specific receptors but correlated with the rapid down-modulation of common NAP-2/IL-8 high affinity binding sites. A similar functional and receptor desensitization was observed in PMN pre-exposed to nonstimulatory doses of NAP-2. Specific inhibition of the CTAP-III-cleaving enzyme by the serine protease inhibitor aprotinin abrogated the CTAP-III, but not the NAP-2-mediated effects. Desensitization of PMN by CTAP-III was due to NAP-2 generated by proteolytic truncation of CTAP-III. Our results suggest that CTAP-III may regulate PMN activation by protecting processing cells from premature activation.
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PMID:Connective tissue-activating peptide III desensitizes chemokine receptors on neutrophils. Requirement for proteolytic formation of the neutrophil-activating peptide 2. 798 67

Situated in secretory granules of cytotoxic cells, granzymes are essential for induction of target cell apoptosis with perforin. However, since cytotoxic cells constitutively secrete a portion of their synthesized granzymes, these proteases could mediate extracellular functions independently of their role in the lytic event. Thrombin has been shown to function as an activation molecule by cleaving its receptor. We hypothesize that granzymes may act similarly. In this report, we show that purified human granzyme A can induce human lung fibroblasts to produce IL6 and IL8. Cytokine induction is abrogated by treating the serine protease with the suicide serine protease inhibitor 3,4-dichloroisocoumarin. Other fibroblast lines as well as epithelial cells produced cytokines in response to granzyme A. Our data suggest that granzyme A can function as an activation molecule with potentially important immunoregulatory functions.
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PMID:Extracellular Activities of Human Granzymes 866 Aug 52

Situated in secretory granules of cytotoxic cells, granzymes are essential for induction of target cell apoptosis with perforin. However, since cytotoxic cells constitutively secrete a portion of their synthesized granzymes, these proteases could mediate extracellular functions independently of their role in the lytic event. Thrombin has been shown to function as an activation molecule by cleaving its receptor. We hypothesize that granzymes may act similarly. In this report, we show that purified human granzyme A can induce human lung fibroblasts to produce IL6 and IL8. Cytokine induction is abrogated by treating the serine protease with the suicide serine protease inhibitor 3,4-dichloroisocoumarin. Other fibroblast lines as well as epithelial cells produced cytokines in response to granzyme A. Our data suggest that granzyme A can function as an activation molecule with potentially important immunoregulatory functions.
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PMID:Extracellular activities of human granzymes. I. Granzyme A induces IL6 and IL8 production in fibroblast and epithelial cell lines. 875 61

To characterize mechanisms which may determine the fate of apoptotic cells, we investigated chemokine expression in apoptotic promonocytic U937 cells or peripheral blood mononuclear cells (PBMC). Exposure of U937 cells to etoposide (VP-16) or the nitric oxide (NO) donor DETA-NO, both inducers of apoptosis in these cells, was associated with increased expression of the chemokines IL-8 and macrophage inflammatory protein-1 alpha. Up-regulation of IL-8 mRNA expression by VP-16 or DETA-NO was observed as early as 4 h or 6 h, respectively, after onset of treatment and was still detectable after 19 h of exposure. A serine protease inhibitor prevented both VP-16-induced apoptosis and release of IL-8, whereas inhibition of p38 MAP kinases reduced IL-8 secretion only. Moreover, we observed that incubation with 2-chlorodeoxyadenosine (CdA) up-regulated release of IL-8 from adherent PBMC in parallel to induction of apoptosis. In these cells a modest but significant induction of TNF-alpha release by CdA was also detected. In addition, CdA augmented release of IL-8 from whole blood cultures. By facilitating adequate recruitment of phagocytes to sites of cell death, stress-induced up-regulation of chemokines associated with apoptosis may contribute to mechanisms aiming at efficient removal of apoptotic cells.
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PMID:Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells. 1054 Mar 34

Mast cells (MC) are strategically located along blood vessels and, on activation, exocytose granules that contain many vasoactive mediators. Endothelial cell (EC) activation, which includes the production of such cytokines as interleukin-6 (IL-6) and IL-8, is a key event in vascular inflammation. In this study, the effects of purified MC granules (MCG) on the production of IL-6 and IL-8 by human coronary artery EC (HCAEC) were examined. HCAEC were cocultured with MCG in the presence or absence of lipopolysaccharide (LPS), and IL-6 and IL-8 levels in the culture medium were assayed by ELISA. Unactivated HCAEC produced only low levels of IL-6 or IL-8, and the addition of MCG alone resulted in little or no increase in production of these cytokines. LPS-activated HCAEC produced significant amounts of IL-6 and IL-8 in a dose-dependent and time-dependent fashion, which was amplified 2-3-fold by MCG at EC/MC ratios of 16:1-2:1. Scanning electron microscopy revealed direct communication between MCG and HCAEC. The enhancement of IL-6 and IL-8 production by MCG was abrogated when MCG were pretreated with the serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF). These results demonstrate that MCG interaction with HCAEC causes amplification of endotoxin-stimulated cytokine production via serine proteases present in MCG. The synergistic activation of EC by endotoxin and MCG proteases emphasizes the role of MC in amplifying vascular inflammation.
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PMID:Endotoxin and mast cell granule proteases synergistically activate human coronary artery endothelial cells to generate interleukin-6 and interleukin-8. 1080 70

Interleukin-8 (IL-8: CXCL8) and growth related oncogene alpha (GROalpha: CXCL1) are members of the CXC chemokines. In the present study, we explored the functional distinction between these CXC chemokines in the regulation of neutrophil infiltration. Injection of either rabbit IL-8 or GROalpha (10 microg each) into rabbit knee joints resulted in a massive neutrophil infiltration in the joints. At their peak time point (6 hours), the number of neutrophils induced by IL-8 was more than that induced by GROalpha. Each chemokine induced the other chemokine in the joints. TNFalpha activity was induced in the joints after administration of GROalpha, but not IL-8. Treatment with anti-GROalpha mAb and/or anti-TNFalpha mAb failed to inhibit IL-8-induced neutrophil infiltration. In contrast, either anti-IL-8 IgG or anti-TNFalpha mAb decreased GROalpha-induced response, and the inhibition was further enhanced by coadministration of these antibodies. Thus, it appears that IL-8 acts directly, whereas GROalpha acts indirectly, in part, on neutrophil infiltration. The distinct difference in TNFalpha production between IL-8 and GROalpha was further investigated. In vitro, GROalpha induced TNFalpha activity in cultured synovial cells, the cells producing TNFalpha in the joints after GROalpha-injection. However, IL-8 failed to produce TNFalpha activity from the cells, although equivalent levels of the mRNA expression were induced by IL-8 as compared with GROalpha. When recombinant rabbit TNFalpha was incubated with synovial fluids obtained at 2 hours after IL-8 injection, the resultant TNFalpha activity was significantly decreased, an event that was completely restored by a serine protease inhibitor, phenylmethylsulphonyl fluoride (PMSF). Furthermore, TNFalpha activity was unveiled in the joints when IL-8 was intra-articularly injected with PMSF. These data suggest that TNFalpha is degraded by serine protease(s) in the case of IL-8. Taken together, the data clearly demonstrate the functional distinction between IL-8 and GROalpha, which may influence the inflammatory responses.
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PMID:Functional distinction between CXC chemokines, interleukin-8 (IL-8), and growth related oncogene (GRO)alpha in neutrophil infiltration. 1179 22

The biological role of most proteases in vivo is largely unknown. Therefore, to develop robust techniques to analyze the protease degradome in cells and tissues and to elucidate their substrate degradomes we have developed a dedicated and complete human protease and inhibitor microarray that we have called the CLIP-CHIP Oligonucleotides (70-mers) for identifying all 715 human proteases, inactive homologs and inhibitors were spotted in triplicate onto glass slides with a dedicated subarray containing oligonucleotides for specific human breast carcinoma genes. Initial analyses revealed the elevated expression of a number of proteases in invasive ductal cell carcinoma including ADAMTS17, carboxypeptidases A5 and M, tryptase-gamma and matriptase-2. Matrix metalloproteinases (MMPs) showed a restricted expression pattern in both normal and cancerous breast tissues with most expressed at low levels. However, of the several MMPs expressed in significant quantities, the carcinoma samples showed only slightly elevated amounts other than for MMP-28 which was strongly elevated. To discover new protease substrates we developed a novel yeast two-hybrid approach we term 'inactive catalytic domain capture' (ICDC). Here, an inactive mutant protease catalytic domain lacking the propeptide was used as a yeast two hybrid bait to screen a human fibroblast cDNA library for interactor proteins as a substrate trap. Wnt-induced signaling protein-2 (WISP-2) was identified by ICDC and was biochemically confirmed as a new MMP substrate. In another approach we used isotope-coded affinity tag (ICAT) labeling with tandem mass spectrometry to quantitate the levels of secreted or shed extracellular proteins in MDA-MB-231 breast carcinoma cell cultures in the presence or absence of membrane type 1-MMP (MT1-MMP) overexpression. By this proteomic approach we identified and biochemically confirmed that IL-8, the serine protease inhibitor SLPI, the death receptor-6, pro-TNF-alpha and CTGF are novel substrates of MT1-MMP. The utility and quantitative nature of ICAT with MS/MS analysis as a new screen for protease substrate discovery based on detection of cleaved or shed substrate products should be readily adaptable to other classes of protease for assessing proteolytic function in a cellular context.
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PMID:Protease degradomics: mass spectrometry discovery of protease substrates and the CLIP-CHIP, a dedicated DNA microarray of all human proteases and inhibitors. 1525 81

While various microorganisms have been recovered from patients with chronic rhinosinusitis, the inflammatory impact of virulence factors, in particular proteases from Staphylococcus aureus and coagulase negative staphylococci on the nasal epithelium, has not yet been investigated. Expression of CXC chemokines was determined in the epithelium of patients with chronic rhinosinusitis by immunohistochemistry. In a cell culture system of A549 respiratory epithelial cells, chemokine levels were quantified by enzyme-linked immunosorbent assay (ELISA) after stimulation with supernatants originating from three different staphylococcal strains or with trypsin, representing a serine protease. Inhibition experiments were performed with prednisolone, with the serine protease inhibitor 4-(2-aminoethyl)-benzenesulphonylfluoride (AEBSF) and with the nuclear transcription factor (NF)-kappaBeta inhibitor (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulphonyl]-2-propenenitrite (BAY) 11-7085. Electromobility shift assays (EMSA) were used to demonstrate NF-kappaB-dependent protein synthesis. CXC chemokines interleukin (IL)-8, growth-related oncogene alpha (GRO-alpha) and granulocyte chemotactic protein-2 (GCP-2) were expressed in the patients' epithelium whereas epithelial cell-derived neutrophil attractant 78 (ENA-78) was rarely detected. In A549 cells, chemokines IL-8, ENA-78 and GRO-alpha but not GCP-2 were induced by trypsin and almost equal levels were induced by staphylococcal supernatants. IL-8, GRO-alpha and ENA-78 synthesis was suppressed almost completely by AEBSF and BAY 11-7085, whereas prednisolone reduced chemokine levels differentially dependent on the supernatant added. CXC chemokines were detectable in the epithelium of patients with chronic rhinosinusitis. Staphylococcal serine proteases induced CXC chemokines in A549 cells, probably by the activation of proteases activated receptors, and thus might potentially be involved in neutrophilic inflammation in chronic sinusitis.
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PMID:Induction of CXC chemokines in A549 airway epithelial cells by trypsin and staphylococcal proteases - a possible route for neutrophilic inflammation in chronic rhinosinusitis. 1673 24

Dermal papilla cells (DPC) control the growth character of the hair follicle through their elaboration of mitogenic factors and extracellular matrix components. Further, the dermal papilla is a primary site of androgen action in the hair follicle. Interleukin-1alpha (IL-1alpha) is prominent in skin wounding and inflammatory responses although regarded as a negative hair growth regulator. We studied the effect of IL-1alpha and the potent androgen 5alpha-dihydrotestosterone (DHT) on the expression of the androgen receptor (AR) and various factors secreted by cultured human temporal scalp DPC. IL-1alpha triggered cellular changes consistent with nuclear factor-kappaB pathway activation as well as reduced AR mRNA and protein expression levels for DHT-stimulated DPC. This cytokine also increased DPC supernatant keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations. IL-1alpha did not influence DPC supernatant levels of transforming growth factor-beta1, a negative hair growth regulator. The stimulatory effect of IL-1alpha on DPC VEGF, GM-CSF, KGF, and IL-8 expression was also evident at the mRNA level for these cytokines. IL-1alpha also increased mRNA transcript levels of protease-nexin-1, a secreted serine protease inhibitor expressed in the dermal papilla of anagen-stage hair follicles. Although DHT did not affect supernatant cytokine concentrations, the androgen altered mRNA transcript levels of several factors for DPC co-stimulated with IL-1alpha. In consideration of its in vitro activity profile, IL-1alpha may be an important modifier of dermal papilla activity as well as potentially influence androgen-regulated gene expression in DPC.
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PMID:Influence of interleukin-1alpha on androgen receptor expression and cytokine secretion by cultured human dermal papilla cells. 1698 60


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