Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We undertook a study to determine whether cytokines exist which are responsible for the activation of polymorphonuclear neutrophilic granulocytes (PMN) besides the already well-known stimuli. Lucigenin-dependent chemiluminescence was used to measure human PMN activation. Addition of supernatants from mononuclear cells stimulated with bacterial lipopolysaccharide produced a long-lasting activation of granulocytes. Induction of chemiluminescence was dose-dependent and inhibitable by superoxide dismutase. Fractionation of mononuclear cells by adherence to plastic dishes or counterflow elutriation proved that monocytes were able to generate granulocyte-activating mediators (GRAM). Production of GRAM was dependent on the dose of the stimulus and appeared to be maximal after 24 h of incubation. Addition of cycloheximide resulted in significantly decreased release of GRAM. Partial characterization of the activity showed GRAM to be heat-labile and sensitive to trypsin, indicating a protein nature of GRAM. The activity fractionated into 2 distinct peaks, one corresponding to 60 kD and another below 10 kD. The interleukin 1 activity did not appear to co-fractionate with GRAM. Evidence presented suggests that the activity corresponds to factors unlikely to have been described previously.
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PMID:Granulocyte-activating mediators (GRAM): I. Generation by lipopolysaccharide-stimulated mononuclear cells. 352 11

A monoclonal antibody was developed against an 8,000-kDa enzyme-releasing peptide (ERP) released from human alveolar macrophages. ERP was isolated on an immunoaffinity column containing the antibody bound to staphylococcal protein A-Sepharose. Release of ERP from the macrophages is not changed by plastic adherence, phagocytosis, calcium ionophore, or phorbol esters. The peptide was not antigenically similar to interferon-gamma, tumor necrosis factor, or interleukin 1 alpha or 1 beta. The release of constituents from azurophilic and specific granules was the main identified biologic function of ERP. ERP was a more effective secretagogue in the untreated neutrophils and f-met-leu-phe was more effective in the cytochalasin B-treated neutrophils. Absorption of ERP from macrophage-conditioned medium removed a small amount of the chemotactic activity; however, the immunopurified peptide was not chemotactic or chemokinetic for neutrophils, and at high concentrations, it suppressed base line chemokinesis. Treatment of washed macrophages with trypsin released active ERP of approximately the same m.w. of spontaneously secreted ERP. These studies showed that human alveolar macrophages release a peptide which is a secretagogue for human neutrophils under conditions which may be encountered in the lungs during certain disease states. Proteolytic enzymes which are free in the lungs may release the peptide and lead to the secretion of neutrophil enzymes.
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PMID:A peptide secreted by human alveolar macrophages releases neutrophil granule contents. 368 Sep 45

The structure of the protein core of the high molecular weight aggregating proteoglycan from pig laryngeal cartilage has been investigated. Mild trypsin digestion of proteoglycan aggregates released a large (Mr approximately equal to 150K) protein-rich fragment that contained the hyaluronate-binding region (Mr 66K). Rotary-shadowing electron microscopy of this preparation showed it to contain 'double globe' structures, similar to those seen with intact proteoglycans. Interaction studies and immunochemical evidence showed that one of the globular domains was the binding region. The second globular domain did not interact with hyaluronate or share any major antigenic determinants with the binding region and its function remains unknown. Further evidence from rotary shadowing also suggested that the protein core contained a third globular domain at the C-terminal end. The complete protein core sequence thus contains long folded globular protein regions, in addition to the extended regions bearing glycosaminoglycan chains. Studies of proteoglycan turnover in explants of pig articular cartilage showed that proteoglycan fragments were continuously released into the medium during culture. These included large non-aggregating proteoglycan fragments, free binding region and also link protein. Proteoglycans retained within the cartilage matrix remained intact and able to aggregate. Only in the presence of interleukin 1 was there evidence of more extensive proteolytic digestion. The results suggest normal turnover to be a conservative mechanism involving the selective cleavage of proteoglycan close to the hyaluronate-binding region. This releases the major glycosaminoglycan-bearing domain and enables it to diffuse out of the matrix. The site of the initial cleavage appears to be in the region of the N-terminal globular domains.
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PMID:Cartilage proteoglycans. 381 21

Human urine contains a specific inhibitor of interleukin 1 (IL 1) that is found in increased amounts during fever. This inhibitor was purified by using a sequence of ammonium sulfate fractionation, DEAE cellulose ion-exchange chromatography, molecular sieve chromatography on Sephacryl S-200, affinity chromatography on concanavalin A (Con A) Sepharose, and polyacrylamide gel electrophoresis. Two peaks of IL 1 inhibitory material were eluted from the polyacrylamide gels. One peak contained three proteins of 29, 32, and 67 kd, respectively, which could be visualized by silver staining. The second peak contained only a small amount of the 67 kd protein. A partially purified inhibitor fraction was found to cross-react with antisera directed against two low m.w. urine trypsin inhibitors that are cleavage products of the serum inter-alpha-trypsin inhibitor. Although these findings suggest that the urine IL 1 inhibitor may be related to the inter-alpha-trypsin inhibitor, a more exact identification will require either a homogeneous inhibitor preparation or a monospecific antiserum.
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PMID:Characterization of a human interleukin 1 inhibitor. 387 5

We and others have previously reported that human blood mononuclear cells release in culture certain substances that enhance the capacity of purified human blood eosinophils to kill the antibody-coated larvae of Schistosoma mansoni. The present study shows that this eosinophil cytotoxicity-enhancing activity (ECEA) is released by monocytes and T lymphocytes. Monocytes produce ECEA in resting and in LPS-stimulated cultures; T lymphocytes release such activity when stimulated by mitogens such as concanavalin A. Furthermore, the human monocytic line U-937 also releases ECEA-like activity when stimulated by LPS. The enhancing activity produced by monocytes has been partially characterized: it is sensitive to proteolysis by trypsin, relatively heat stable, and associated with molecules that have an apparent molecular weight of 14,000 to 65,000 daltons and isoelectric points of 3.8-3.9, 4.2, 4.5, 4.8-4.9. This shows that while ECEA produced by monocytes is heterogeneous in size and charge, it is probably different from interleukin 1.
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PMID:Activation of human eosinophils by monokines and lymphokines: source and biochemical characteristics of the eosinophil cytotoxicity-enhancing activity produced by blood mononuclear cells. 387 17

Two separate cultures of pure, morphologically distinct thymic epithelial cells have been generated and maintained in culture for one year (A.C. Nieburgs et al., Cell. Immunol. 90, 439-450, 1985). Supernatants from one of these cell lines, TECs, were examined for functional activity on thymocytes in vitro. These supernatants contained three distinct intercellular mediators, each capable of modulating thymocyte responses to T-cell mitogens. Enhancement of thymocyte proliferation to suboptimal doses of mitogen was associated with a factor that eluted in the 97,000-Da region on molecular sieve chromatography and was functionally and physicochemically distinct from interleukin-1 and interleukin-2 (IL-1 and IL-2). Suppression of the thymocyte response to optimal doses of mitogen was mediated by a 1000- to 5000-Da factor. These two intercellular components have different susceptibilities to heat treatments and are trypsin insensitive. In addition, thymic epithelial cells produced significantly high levels of prostaglandin E2 (PGE2) which also suppressed thymocyte responses to mitogen, but only at high doses of supernatant. These epithelial cell-derived enhancing and inhibitory effects on thymocytes could play a role in regulating intrathymic events.
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PMID:The production of regulatory cytokines for thymocyte proliferation by murine thymic epithelium in vitro. 388 Nov 91

The human monocytic leukemia cell line THP-1 produces an immunosuppressive factor that inhibits interleukin 1 (IL-1)-dependent proliferation of mouse thymocytes as well as the mitogenic effects of concanavalin A (Con A) and phytohemagglutinin (PHA) on human peripheral blood mononuclear cells. The mechanism of action of this factor includes interference with both the production of interleukin 2 (IL-2) and its effects on target cells. Thus, the suppressor abrogates the proliferation of an IL-2-dependent cytotoxic T cell line (CTLL), but not of IL-2 independent cells like the L929 fibroblasts or the EL4 T lymphoma and U937 histiocytic lymphoma lines. It also suppresses IL-2 production by human peripheral blood enriched T cells and mouse splenocytes. The mediator has a molecular weight of 60,000-70,000 dalton, as determined by gel filtration chromatography, is heat labile, and is sensitive to trypsin, chymotrypsin, and protease.
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PMID:A macrophage-derived factor that inhibits the production and action of interleukin 2. 389 22

Neutrophil granulocytes are most active producers of potentially toxic free oxygen radicals. Since other functions of granulocytes can be affected by lymphokines or monokines, we investigated whether granulocyte oxygenation activity can also be influenced by such cellular mediators. Human granulocytes emitted strong chemiluminescence after addition of culture supernatants from human mononuclear cells stimulated with bacterial lipopolysaccharide (LPS). Response of the granulocytes was dose-dependent and was inhibited up to 90% or more by superoxide dismutase. This granulocyte chemiluminescence inducer-activity (GCI-activity) in the LPS-induced supernatants was heat-labile and sensitive to trypsin treatment. Addition of cycloheximide to the cultures inhibited the generation of GCI-activity by 80%. On HPLC gel filtration GCI-activity eluted with two distinct peaks corresponding to molecular weights of 60 +/- 10 KDa and between 1 and 5 KDa. Murine interleukin 1, human recombinant interferon-alpha and -gamma were devoid of GCI-activity. When mononuclear cells were fractionated by plastic adherence or counterflow elutriation, monocytes appeared to be the source of GCI-activity. Therefore, it appears that granulocyte oxygenation activity can be enhanced strongly by a cellular mediator derived from monocytes. This interaction of monocytes and granulocytes may constitute a new and potent pathway of phagocyte-dependent production of highly reactive and potentially toxic oxygen radicals.
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PMID:Induction of granulocyte chemiluminescence by a mediator derived from human monocytes. 394 6

Changes in the macromolecular proteolycan (PG) and collagen of the cartilage matrix may culminate in irreparable tissue destruction. Molecular modifications appear to result from: (A) exogenous proteinases, (B) endogenous chondrocyte proteinases whose synthesis and release is modulated by exogenous non-enzymatic cytokines (CKs) and (C) quantitative and/or qualitative alterations in chondrocyte PG and collagen synthesis which are potentially induced by exogenous CKs. Studies have recently been initiated to determine the effect of piroxicam on the synthesis and activity of such metabolic regulatory CKs in patients with rheumatoid arthritis and osteoarthritis, and in age-, sex-, and race-matched controls. Therapeutic doses of piroxicam alone had no effect on the anabolic or catabolic function of chondrocytes. Current studies concern the effect of piroxicam on: (a) spontaneous and lectin-driven production by peripheral blood monocytes and T-cells of trypsin-sensitive, heat-labile CKs (interleukin 1, lymphokine) which, in a protein- and RNA-synthesis-dependent manner, induce a concentration and duration of substrate exposure dependent release of chondrocyte PG- and collagen- degrading neutral proteinases in cartilage organ and chondrocyte suspension culture systems; (b) spontaneous and lectin-driven synthesis by peripheral blood T-cells of lymphokines capable of suppressing chondrocyte PG, glycosaminoglycan, protein, collagen and nucleic acid synthesis in a quantitatively reversible manner; (c) pathological synovial membrane synthesis of such catabolic-inducing and anabolic-modulatory CKs. These experimental model system are reviewed together with preliminary data on the effect of piroxicam.
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PMID:Cytokine modulation of chondrocyte metabolism--in vivo and in vitro effects of piroxicam. 638 36

In previous studies, cultured melanoma cells were shown to have a suppressive influence on the induction of cytotoxic T cells. Our investigation of the mechanism of these effects revealed that supernatants from certain cultures of melanoma cells contained inhibitory activity against the production of interleukin 2 (IL 2) from phytohemagglutinin (PHA)-stimulated cultures of lymphocytes. These supernatants did not inhibit interleukin 1 production, and also did not inhibit the mitogenic activity of performed IL 2 on IL 2-dependent target cells. Production of the inhibitory activity could be reduced by inhibitors of protein synthesis, but this activity was not inhibited by digestion with the proteolytic enzymes trypsin or pronase. Gel filtration analysis of tumor supernatants revealed that the majority of the inhibitory activity was detected in fractions of approximately 44 and 7 Kd. The addition of supernatants with inhibitory activity to PHA-stimulated cultures of lymphocytes was associated with reduced transition of cells from G1 to S phase of cell division, which could be reversed by the addition of IL 2. Preliminary studies suggest that the release of the factor(s) from melanoma cells may be related to rapid progression of tumor growth in patients, and therefore may be of prognostic significance in tumor host relationships.
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PMID:Inhibition of interleukin 2 production by factors released from tumor cells. 660 93


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