Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice pretreated by intravenous injection of 42 mg/kg of the serine protease inhibitor alpha 1-antitrypsin prior to a hepatotoxic dose of D-galactosamine/lipopolysaccharide (GalN/LPS) were fully protected against hepatitis. Pretreatment with alpha 1-antitrypsin with doses up to 300 mg/kg at different times failed to protect galactosamine sensitized animals against tumor necrosis factor alpha (TNF alpha)-induced hepatitis. No bioactive TNF alpha was detectable in serum of mice protected against GalN/LPS-induced hepatitis by pretreatment with alpha 1-antitrypsin. In contrast, abundant amounts of TNF were found in sera of GalN/LPS-treated control animals. It is concluded that a serine protease sensitive to alpha 1-antitrypsin provides bioactive TNF alpha by proteolytic cleavage of a TNF alpha precursor.
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PMID:In vivo evidence for protease-catalysed mechanism providing bioactive tumor necrosis factor alpha. 222 15

We described in a foregoing report findings on serpin, a serine protease inhibitor, newly identified in horseshoe crab (Tachypleus tridentatus) hemocytes and we name it limulus intracellular coagulation inhibitor, LICI (Miura, Y., Kawabata, S., and Iwanaga, S. (1994) J. Biol. Chem. 269, 542-547). This serpin specifically inhibits limulus lipopolysaccharide-sensitive serine protease, factor C. In ongoing studies on limulus serpin, we have found another inhibitor, LICI type-2 (LICI-2), which inhibits not only factor C (k1 = 7.1 x 10(4) M-1 S-1) but also limulus clotting enzyme (k1 = 4.3 x 10(5) M-1 S-1). LICI-2 inhibits mammalian serine proteases, including alpha-thrombin, salivary kallikrein, plasmin, and tissue plasminogen activator. The inactivation of plasmin is the most rapid (k1 = 1.2 x 10(6) M-1 S-1). The purified LICI-2 is a single chain glycoprotein with an apparent M(r) = 42,000. A cDNA for LICI-2 was isolated and the open reading frame coded for a mature protein of 386 amino acids, of which 160 residues were confirmed by peptide sequencing. Although LICI-2 shows significant sequence similarity to the previous limulus serpin, LICI-1 (42% identity), LICI-2 contains a unique putative reactive site, -Lys-Ser-, distinct from that of LICI-1 (-Arg-Ser-). Northern blotting revealed expression of LICI-2 mRNA only in hemocytes, and not in heart, brain, stomach, intestine, coxal gland, and skeletal muscle. The immunoblot of large and small granule components with antiserum against purified LICI-2 suggests that LICI-2 is stored specifically in large granules, as in the case of LICI-1, and is released in response to external stimuli. We propose that the LICIs be classified into a new subfamily of intracellular serpins, regulated secretory serpins.
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PMID:A limulus intracellular coagulation inhibitor type 2. Purification, characterization, cDNA cloning, and tissue localization. 782 80

The effects of mast cell granules (MCGs) on macrophage-mediated lysis of P815 mastocytoma cells and nitric oxide (NO) production were studied. Murine peritoneal macrophages exhibited tumor cell killing and NO production only when activated with lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma). Coincubation of macrophages with MCGs during LPS activation dose-dependently inhibited macrophage-mediated tumor cell lysis. The MCG effect was not due to inactivation or removal of LPS by MCG. The inhibitory effect was also not due to histamine or serotonin present in the MCGs. The granules were not toxic to macrophages or P815 mastocytoma cells. The effect of MCGs on macrophage-mediated tumor cell killing was evident whether MCGs were added before or after a 4-h exposure of macrophages to LPS. However, the inhibitory effect was not seen if MCGs were added after macrophages had been exposed to LPS for 24 h. To assess whether MCGs could inhibit a non-LPS trigger, MCGs were tested on macrophages activated with IFN-gamma. In these experiments, MCGs dose-dependently inhibited macrophage-mediated tumor cell killing induced by IFN-gamma, LPS, or IFN-gamma plus LPS. Furthermore, in parallel experiments, MCGs significantly inhibited macrophage NO production induced by LPS, IFN-gamma, or IFN-gamma plus LPS. Pretreatment of MCGs with diisopropylfluorophosphate, a serine protease inhibitor, only partially abrogated the effects of MCGs. The results demonstrate that MCGs inhibit both LPS- and IFN-gamma-induced macrophage killing of P815 cells and the inhibition is associated with the decrease of NO production.
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PMID:Mast cell granules inhibit macrophage-mediated lysis of mastocytoma cells (P815) and nitric oxide production. 848 25

Proteases are known to be involved in regulation of macrophage activation and killing. We examined the effect of a serine protease inhibitor, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), on lysis of leukemic cells by human macrophages. Monocytes, isolated by Histopaque gradients and centrifugal elutriation, were cultured for 5 days in RPMI-1640 medium with 5% AB serum, and then activated with interferon-gamma (IFN-gamma; 100 U/mL) and lipopolysaccharide (LPS) (5 ng/mL), with or without AEBSF, for 2 days. On day 7, macrophages were washed, fresh medium without AEBSF added, and target cells added for 2 days. Lytic activity against two leukemic cell lines (K562 and HL-60) was assessed by an 111indium-releasing assay. Macrophages treated with IFN-gamma + LPS lysed K562 and HL-60 cells. AEBSF (50-150 microM) blocked the killing of these leukemic cells in a concentration-dependent manner. Other protease inhibitors were not effective. AEBSF was nontoxic at the concentrations used, and did not inhibit tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion from the macrophages. The lytic activity against leukemic cells was inhibited by anti-TNF-alpha antibody, but not by anti-IL-1 beta, nor by superoxide dismutase or catalase. However, the leukemic cells were resistant to being killed by recombinant TNF-alpha alone in the absence of macrophages, indicating that TNF-alpha was required for killing, but that other factors that were inhibited by AEBSF were also required. Serum-free culture supernatant of activated macrophages had significant cytotoxic activity against leukemic cells. This cytotoxic activity was not altered by addition of AEBSF to the culture supernatant, suggesting that AEBSF affected macrophage activation, rather than inhibiting cytotoxic proteases secreted by the macrophages, or affecting the target cells themselves. Thus, a protease, which is susceptible to AEBSF, might be involved in the activation of macrophages, and might regulate the secretion of antitumor effector molecules other than TNF-alpha.
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PMID:Lysis of leukemic cells by human macrophages: inhibition by 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor. 883 Jul 89

1. In view of the potential deleterious effects of high amounts of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS) in inflammation, the prevention of the expression of this enzyme represents an important therapeutic goal. In cytokine-stimulated cells, activation of nuclear factor kappa B (NF-kappa B) is crucial for the increase in iNOS gene expression. Since NF-kappa B activation appears to involve a redox-sensitive step, we have investigated whether three structurally unrelated antioxidants, 5,7-dihydroxyflavone (chrysin), 3,4-dichloroisocoumarin (DCI) and N-acetyl 5-hydroxytryptamine (N-acetylserotonin, NAS), affect iNOS expression in cultured RAW 264.7 monocyte/macrophages stimulated with bacterial lipopolysaccharide (LPS, 140 ng ml-1) and interferon-gamma (IFN gamma, 5 u ml-1). 2. During a 6 h incubation period neither LPS nor IFN gamma alone exerted a significant effect but when combined, caused a prominent increase in nitrite formation, iNOS mRNA and protein abundance. Co-incubation with chrysin (50 microM), DCI (50 microM) or NAS (1 mM) markedly attenuated this increase in iNOS gene expression. 3. DCI, but not chrysin or NAS, prevented the activation of NF-kappa B in cells exposed to LPS plus IFN gamma for 30 min. In contrast, all three antioxidants significantly blunted the DNA-binding activity of interferon regulatory factor 1 (IRF-1), which mediates the synergistic effect of IFN gamma on iNOS gene expression in cells treated for 2 h with LPS plus IFN gamma. 4. DCI thus appears to inhibit iNOS gene expression at the transcriptional level by preventing the activation of both NF-kappa B and IRF-1. The inhibitory effect of DCI on NF-kappa B activation, however, does not seem to be related to its antioxidative properties, since DCI, unlike chrysin or NAS, is a potent serine protease inhibitor which stabilizes the inactive NF-kappa B complex by protecting the inhibitory I kappa B-alpha subunit from proteolytic degradation. 5. The virtually identical inhibitory effect of chrysin, DCI and NAS on the activation of IRF-1 points to a redox-sensitive step in the activation of this transcription factor, which in contrast to NF-kappa B requires de novo protein synthesis. 6. Since iNOS gene expression in human cells and tissues usually requires the combination of several cytokines, antioxidants such as chrysin and NAS which do not interfere with the activation of NF-kappa B may be of therapeutic value for selectively inhibiting the enhanced expression of this enzyme in inflammation.
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PMID:Inhibition by antioxidants of nitric oxide synthase expression in murine macrophages: role of nuclear factor kappa B and interferon regulatory factor 1. 886 59

E-Selectin is an inducible, endothelium-specific, cell surface adhesion molecule that mediates inflammatory responses in the vasculature. Nonendothelial cell types such as cultured human aortic smooth muscle cells (HASMCs) lack the ability to express E-selectin. We tested the hypothesis that HASMCs express a negative regulatory factor that inhibits E-selectin gene expression. E-Selectin mRNA and gene transcription were not detected in HASMCs after treatment with tumor necrosis factor-alpha (TNF-alpha) by Northern and nuclear runoff analyses, respectively. However, both E-selectin mRNA and gene transcription were dramatically induced by TNF-alpha in the same cells pretreated with the protein synthesis inhibitor cycloheximide. Lipopolysaccharide demonstrated similar effects. Furthermore, E-selectin was detected on the cell surface of HASMCs after washing out of cycloheximide. Cycloheximide pretreatment enabled immortalized human dermal microvascular endothelial cells that have lost the ability to express E-selectin to induce both E-selectin mRNA and gene transcription in response to TNF-alpha. Induction of E-selectin mRNA by lipopolysaccharide or TNF-alpha in cycloheximide-treated HASMCs was inhibited by the antioxidant pyrrolidinedithiocarbamate and the serine protease inhibitor N alpha-L-tosyl-L-phenylalanine chloromethyl ketone, suggesting that a nuclear factor-kappa B-like mechanism may play an important role in E-selectin gene expression in HASMCs. These data strongly suggest that a labile repressor protein(s) plays an important role in inhibiting E-selectin gene expression in HASMCs likely at the level of gene transcription. Except for this repressor, HASMCs and endothelial cells may share similar regulatory mechanisms for controlling E-selectin expression.
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PMID:E-selectin gene expression in vascular smooth muscle cells. Evidence for a tissue-specific repressor protein. 904 49

Infection of humans with Shiga toxin-producing Escherichia coli O157:H7 and Shigella dysenteriae 1 is strongly associated with vascular endothelial cell damage and the development of hemolytic-uremic syndrome. The cytotoxic effect of Shiga toxins on vascular endothelial cells in vitro is enhanced by prior exposure to bacterial lipopolysaccharide (LPS) or either of the host cytokines tumor necrosis factor alpha (TNF) and interleukin-1beta (IL-1). The purpose of this study was to examine individual signal transduction components involved in the sensitization of human umbilical vein endothelial cells (HUVEC) to Shiga toxin 1. The results demonstrate that class I and II protein kinase C (PKC) isozymes are required for sensitization of HUVEC to Shiga toxin by phorbol myristate acetate (PMA) or LPS but not by TNF or IL-1. Thus, the specific competitive inhibitor of class I/II PKC, 1-O-hexadecyl-2-O-methyl-rac-glycerol (AMG), prevented only the action of PMA and LPS on HUVEC. Additional data obtained with ATP binding site inhibitors which affect all PKCs (i.e., classes I, II, and III) suggest that TNF may utilize class III PKC isozymes in the Shiga toxin sensitization of HUVEC. Transcriptional activator NF-kappaB did not appear to be involved in the sensitization of HUVEC to Shiga toxin by LPS, TNF, IL-1, or PMA. Thus, the specific serine protease inhibitor L-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK) did not inhibit the sensitization of HUVEC to Shiga toxin by LPS, TNF, IL-1, or PMA despite its ability to inhibit NF-kappaB activation and the induction of the NF-kappaB-dependent tissue factor gene by these agents. Finally, all-trans retinoic acid partially inhibited the sensitization of HUVEC to Shiga toxin, by unknown mechanisms which also appeared to be independent of NF-kappaB activation. These results indicate that PKC plays a role in the sensitization of HUVEC to Shiga toxin in response to some, but not all, sensitizing agents. In contrast, NF-kappaB activation appears not to be involved in the sensitization of HUVEC to Shiga toxin by LPS, TNF, IL-1, or PMA.
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PMID:Sensitization of human umbilical vein endothelial cells to Shiga toxin: involvement of protein kinase C and NF-kappaB. 923 95

We evaluated the effect of antithrombin III (ATIII), a serine protease inhibitor (SERPIN), on induction of nitric oxide (NO) synthesis in murine peritoneal macrophages. Incubation of macrophages with ATIII plus interferon-gamma (IFN-gamma) but not ATIII alone induced nitrite accumulation (a metabolite of NO) in a dose-dependent manner. Expression of the inducible nitric oxide synthase isoform was confirmed by Western blot. NO synthesis was inhibited by NG-monomethyl-l-arginine, by complexing ATIII with thrombin or by rabbit anti-human ATIII antiserum. Addition of polymyxin B to macrophage cultures failed to inhibit ATIII/IFN-gamma-induced NO synthesis, excluding lipopolysaccharide contamination. 125I-ATIII bound to macrophages in a dose-dependent, specific, and saturable manner, with a Km of approximately 7.1 nM. Our results demonstrate that ATIII, but not ATIII/thrombin complex, acts to costimulate macrophage activation and NO synthesis via a novel receptor mediated mechanism, which may indicate a role for SERPINs in macrophage activation.
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PMID:Receptor-mediated activation of murine peritoneal macrophages by antithrombin III acts as a costimulatory signal for nitric oxide synthesis. 974 55

We investigated the effect of FUT-175, a serine protease inhibitor, on the production of pro-inflammatory cytokines, interleukin-6 (IL-6) and interleukin-8 (IL-8), by monocytes stimulated with lipopolysaccharide (LPS). Monocytes isolated from healthy volunteers were incubated with LPS and various concentrations of FUT-175 for 12 hours. The productions of both IL-6 and IL-8, measured by enzyme-linked immunosorbent assay, were significantly inhibited by FUT at the concentration of 1 to 100 microg/ml in a dose-dependent manner. Furthermore, the expressions of IL-6 and IL-8 mRNAs were also inhibited by FUT-175. These data suggest that FUT-175 may reduce the pathological inflammatory conditions associated with enhanced production of proinflammatory cytokines including IL-6 and IL-8.
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PMID:FUT-175 inhibits the production of IL-6 and IL-8 in human monocytes. 1044 May 71

Secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor abundantly found in mucous secretions of lung, is thought to serve as an important protective component in the secretory fluids at sites of degenerative and inflammatory diseases. In this study, we examined the effects of SLPI on the production of a proinflammatory cytokine, TNF-alpha, and immunosupressive cytokines, IL-10 and transforming growth factor-beta (TGF-beta) by macrophages (M phi s), in response to lipopolysaccharide (LPS)-mediated stimulation and M. avium complex (MAC) infection, using recombinant half-sized SLPI (1/2 SLPI) consisting of C-terminal domain (Arg55-Ala107) of intact SLPI. In addition, effects of SLPI on the production of nitric oxide radicals (NO), important antimicrobial effectors of M phi s against micro-organisms, by these M phi s were studied. First, when the number of TNF-alpha producing cells in the LPS-stimulated M phi population was counted by the ELISPOT assay, more than half of the M phi s acquired TNF-alpha secreting ability at 24 hr after LPS stimulation. On the other hand, MAC-infected M phi s produced detectable amounts of TNF-alpha into culture fluid during the first 24 hr. In both cases, 1/2 SLPI did not affect the LPS- or MAC-induced TNF-alpha production by M phi s. Second, when the production of IL-10 and TGF-beta by M phi s was determined by measuring the amounts of these cytokines accumulated in M phi culture fluids by ELISA, the following was observed. M phi IL-10 production was rapidly increased in the early phase of cultivation after LPS stimulation or MAC infection, peaking on day 1 and thereafter declining to normal level by day 14. Half-sized SLPI did not affect IL-10 production of LPS-stimulated M phi s, while it caused slight enhancement of IL-10 production by MAC-infected M phi s. M phi TGF-beta production was initiated in the middle phase (day 7) of M phi cultivation and continued until day 14. Notably, 1/2 SLPI markedly potentiated the TGF-beta producing ability of the LPS-stimulated M phi s. Moreover, 1/2 SLPI caused moderate increase in the TGF-beta production by MAC-infected M phi s. Third, significantly potentiated NO production was observed in M phi s during the first 2 days after LPS stimulation and MAC infection. Half-sized SLPI did not affect the NO production by LPS-stimulated or MAC-infected M phi s. These findings indicate that SLPI up-regulates the production of some immunoregulatory cytokines including IL-10 and TGF-beta, particularly the latter, by M phi s in response to LPS stimulation or MAC infection, thereby suggesting the possibility that SLPI may exhibit antiinflammatory effects in vivo, especially patients with bacterial infections including MAC diseases, through the modulation of M phi expression of some immunosuppressive cytokines.
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PMID:[Effects of secretory leukocyte protease inhibitor on the production of some cytokines and nitric oxide by murine peritoneal macrophages in response to lipopolysaccharide stimulation and M. avium complex infection]. 1048 11


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