Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Ovine lentiviruses share genome sequence, structural features, and replicative mechanisms with HIV, the etiologic agent of AIDS. A lamb model of lentivirus-induced lymphoid interstitial pneumonia, comparable to lymphoid interstitial pneumonia associated with pediatric AIDS, was used to investigate production of leukocyte-soluble mediators. Lentivirus-infected lambs and adult sheep with severe lymphoid interstitial pneumonia had significantly elevated levels of spontaneous interferon (IFN) production from pulmonary leukocytes compared with ovine lentiviruses-infected animals with mild or no lesions of lymphoid interstitial pneumonia or non-infected controls. However, peripheral blood mononuclear cells from lentivirus-infected lambs did not spontaneously release significant amounts of IFN. IFN production by pulmonary lymph node lymphocytes was enhanced in the presence of lentivirus-infected alveolar macrophages. Animals with lentivirus-induced disease and spontaneous IFN production had enhanced virus replication within tissues. The ovine lentiviruses-induced IFN had a m.w. of between 25,000 and 35,000 and was resistant to freeze/thawing procedures. The IFN activity was sensitive to trypsin and stable to low pH and heat. IFN with similar physical and biochemical properties was produced when ovine lentiviruses was added to control leukocyte cultures. IL-2 and PGE2 production and responses to mitogen by pulmonary lymph node lymphocytes of lentivirus-diseased lambs were not statistically different from control animals. Increased local production of IFN in lentivirus-infected host tissues may serve to accelerate the entry of leukocytes into virus-induced lesions promoting cell-mediated tissue damage and also provide increased numbers of cells for virus replication.
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PMID:Spontaneous interferon production by pulmonary leukocytes is associated with lentivirus-induced lymphoid interstitial pneumonia. 244 76

A 549, a human lung cancer cell line, spontaneously produces a tumor-derived immunosuppressive factor (TDSF) which inhibited PHA-stimulated T lymphocyte proliferation via a noncytotoxic mechanism. The inhibition increased in a dose-dependent pattern. The factor also markedly suppressed production of interleukin (IL-2) by PHA-stimulated lymphocytes and IL 2-dependent proliferation of activated lymphocytes. The fact that TDSF possessed very potent inhibitive action on IL-2 is especially noteworthy if we consider the use of IL-2 as immunotherapeutic agent. The synthesis of the factor was inhibited by mitomycin C, actinomycin D and cycloheximide, indicating that the factor is a genic product of A 549 cells. The factor is chemically a protein with a molecular weight greater than 150 KD and sensitive to extremes of pH, heating to 60 degrees C and trypsin treatment.
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PMID:Biologic characteristics of an immunosuppressive factor derived from a human lung cancer cell line. 260 Sep 79

We have identified a late, committed stage in the differentiation of the mast cell progenitor just before granulation. Mast cell committed progenitors (MCCP) are nongranulated cells with a density of 1.060 to 1.070 g/ml which can be harvested from the mesenteric lymph node of mice infected with Nippostrongylus brasiliensis. Mast cell-committed progenitors are able to proliferate and differentiate in the absence of IL-3 or IL-4 when cultured on a monolayer of embryonic skin or 3T3 fibroblasts and can form colonies in methylcellulose supplemented with fibroblast conditioned medium. Fibroblast conditioned medium appears to contain a soluble MCCP proliferation factor that maintains biologic activity when heated to 56 degrees C for 45 min but is destroyed by incubation with either trypsin or chymotrypsin. It can be selectively precipitated with 60 to 70% saturated ammonium sulfate. The factor is not absorbed by immobilized antibodies to nerve growth factor. The MCCP proliferation activity of the factor could not be mimicked by IL-1, IL-2, IL-4, granulocyte-macrophage-CSF, granulocyte-CSF, macrophage-CSF, IFN-alpha/beta, IFN-gamma, nerve growth factor, epidermal growth factor, serum fibronectin, heparin, or a number of glycosaminoglycans. At high salt concentrations, the factor passes through a 50-kDa membrane and can be concentrated above a 5-kDa membrane. MCCP acquire a connective tissue phenotype when cultured on a fibroblast monolayer and a mucosal phenotype when cloned in the presence of conditioned medium from PWM-stimulated spleen cells. When cultured in the absence of IL-3 on a monolayer of embryonic skin or 3T3 fibroblasts, mast cell-committed progenitors produce mast cells which stain with berberine sulfate suggesting a connective tissue phenotype; however, the mast cells that develop when mast cell-committed progenitors are cultured in the presence of IL-3 or conditioned media from PWM-stimulated spleen cells do not stain with berberine sulfate. MCCP intercalate into monolayers of embryonic skin or 3T3 fibroblasts, but T cells are not able to associate with the monolayer and can be completely washed away. Attempts to enrich mast cell-committed progenitors by intercalation and elution from embryonic skin monolayers proved unsuccessful, but some enrichment of mast cell-committed progenitors could be achieved by discontinuous Percoll gradients. Thus, we have identified a way to obtain late-stage, mast cell-committed progenitors in an environment that is virtually uncontaminated with other hematopoietic progenitors.
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PMID:The mast cell-committed progenitor. I. Description of a cell capable of IL-3-independent proliferation and differentiation without contact with fibroblasts. 278 62

The expression of serine protease genes was examined in murine NK cells that were purified by panning spleen cells with PMA. Although unstimulated NK cells were cytolytic, they were found not to express the C11 (chymotrypsin-like) mRNA. Culturing these cells in IL-2 (500 to 800 U/ml) for 5 to 7 days induced both the lytic activities and the protease enzymes by 20- to 30-fold. Concomitant to these activation events, the total steady state mRNA of both C11 and HF (trypsin-like) genes were also elevated. The activation of lysis, serine protease enzymes, and C11 and HF mRNA all peaked around day 5 in culture and was dose dependent. In order to exclude the possibility that PMA synergizes with IL-2 in this system, spleen cells from SCID mice, which contained mainly NK cells, were cultured under the same conditions (800 U/ml IL-2, with or without PMA) and PMA did not appear to enhance the expression of these mRNA. Similarly, IL-2 also induced the lytic activities, enzyme levels, and mRNA in the non-Ag-specific T killer cells isolated from spleens of normal mice. Lytic activity of T killer cells was not as high as the NK cells, however, the addition of PHA into the lytic assay resulted in enhanced lysis comparable to that of NK cells. These results showed that lytic activity increased along with protease enzyme levels and mRNA expression in both NK and resting T cells. Therefore, elevated levels of the protease enzymes could be one mechanism involved in optimal lytic activity of IL-2-induced lymphokine activated killer cells.
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PMID:IL-2 induces expression of serine protease enzymes and genes in natural killer and nonspecific T killer cells. 278 61

A new trypsin-like serine protease was cloned from both a murine cytotoxic T lymphocyte and a human PHA-stimulated peripheral blood lymphocyte cDNA library. In both the mouse and human system, this transcript had a T cell- and NK-specific distribution, being detected in cytotoxic T lymphocytes (CTL), some T-helper clones, and NK, but not in a variety of normal tissues. T-cell activation with Con A plus IL-2 induced mouse spleen cells to express this gene with kinetics correlating with the acquisition of cytolytic capacity. Both the mouse and human nucleotide sequences of this gene encoded an amino acid sequence with 25-40% identity to members of the serine protease family. The active-site "charge-relay" residues (His-57, Asp-102, and Ser-195 of the chymotrypsin numbering system) are conserved, as well as the trypsin-specific Asp (position 189 in trypsin). We reviewed the evidence of this serine protease's role in lymphocyte lysis and proposed a "lytic cascade." We discussed the biological and clinical implications of a cascade, proposing these enzymes as markers for cytolytic cells and as targets for rational drug therapy. Genetic and acquired deficits in the lethal hit-delivery system are considered as a basis for approaching some immunodeficiency states, including severe EBV infections, T-gamma leukemias, and T8+ lymphocytosis syndromes.
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PMID:A T cell- and natural killer cell-specific, trypsin-like serine protease. Implications of a cytolytic cascade. 305 12

High-affinity receptors for IL-2 (ala 125) were demonstrated in PHA-, antigen- and/or alloantigen-activated human T-cells (both proliferative and cytotoxic), in PWM-activated human B-cells and in human monocyte-macrophages. Binding in PHA-blasts was irreversible and Ca++-independent, and labelled IL-2 (ala 125) bound at 4 degrees C could not be removed by trypsin treatment. Binding was strongly pH-dependent, and lowering of pH caused release of nearly all cell associated radioactivity at 4 degrees C. In T- and B-lymphocytes, additional binding at high ligand concentrations was accounted for by receptors of much lower affinity. Binding to low-affinity receptors appeared reversible. At 4 degrees C, 2.2 pM labelled IL-2 (ala 125) bound to PHA-blasts (3.6 X 10(6)/ml) with a half time of about 15 min, and the association rate constant was approximately 8 X 10(9) M-1 min-1. The number of high affinity receptors per T-cell was determined as 9.7 +/- 0.5 X 10(2). At 37 degrees C, 60% of the tracer bound at 4 degrees C was rapidly internalized (Kint = 0.89 X 10(-1) min-1), and radioactivity comprising small MW products and iodotyrosine was released following a sigmoidal curve after a 20 min lag period. Similar results were obtained in PWM-activated B-lymphocytes and in cultured monocytes. It is concluded that high-affinity receptors mediate binding, uptake and degradation of IL-2 in activated human T- and B-lymphocytes and in monocyte-macrophages.
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PMID:Binding, uptake and degradation of human recombinant interleukin-2 (125 ala) in activated human T- and B-lymphocytes and in monocyte-macrophages. 311 20

Human lymphocytes respond to IL-2 with the generation of MHC-unrestricted oncolytic activity. This function has been named lymphokine-activated killing (LAK). To investigate the mechanism by which IL-2 activates and maintains LAK, we have examined the role(s) of IL-2 cell surface receptors. Removal or blockade of unstimulated lymphocytes expressing the IL-2 receptor Tac does not preclude the acquisition of LAK function. Therefore, a non-Tac IL-2 receptor was proposed to be involved in LAK generation. Using direct 125I-IL-2 binding to Tac-negative LAK precursors suggested the existence of such an alternate IL-2 receptor. Chemical crosslinking of 125I-IL-2 to Tac-depleted lymphocytes followed by SDS-PAGE determined that the size of the non-Tac-binding protein was approximately 75 kDa. Tac-negative lymphocytes activated by a limited IL-2 pulse which was insufficient for detectable Tac upregulation indicated that an initial non-Tac pathway was involved in functional differentiation. The development of lytic function, Tac upregulation, and cellular proliferation was prohibited by trypsin, a treatment shown also to eliminate 125I-IL-2 binding to Tac-negative lymphocytes. The Tac antigen, although not involved in the initial generation of LAK, is involved in the proliferative maintenance of this lytic function.
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PMID:Functional differentiation of human lymphokine-activated killing (LAK) is distinct from expansion and involves dissimilar interleukin 2 receptors. 312 71

Culture supernatants of splenic T cells from susceptible CBA mice chronically infected with Trypanosoma cruzi contain a suppressive substance which can inhibit the induction of delayed-type hypersensitivity (DTH) to a wide range of antigens. The suppressive substance is distinct from T. cruzi antigen inasmuch as the supernatant depleted of any residual T. cruzi antigen by an affinity column still retains the suppressive activity, whereas addition of T. cruzi antigens to control supernatant did not confer suppressive function. The suppressive supernatant does not contain detectable levels of IL-1, IL-2, IL-3, or IFN-gamma but a modest level of IL-1 and IL-2 inhibitory activities. However, both these inhibitory activities elute at a different position from the DTH suppressive activity on gel filtration. The DTH suppressive activity is heat labile (1 h, 56 degrees C), cryostable, but destroyed by trypsin treatment. It binds to ricin but not to lentil lectin. Sepharose 4B gel filtration and HPLC analysis in mild chaotropic agents (urea, ethylene glycol) demonstrate that the suppressive substance has an apparent Mr of 30 to 60 kDa, but full DTH-suppressive activity is retained only in an aggregated form.
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PMID:Suppressive substance produced by T cells from mice chronically infected with Trypanosoma cruzi. II. Partial biochemical characterization. 312 53

In order to study the possible role of alveolar macrophages (AMs) in the development of local immune responses, we compared interleukin-1 (IL-1) production by peripheral blood monocytes and AMs from 17 allergic asthmatics and 32 controls. When stimulated by lipopolysaccharide, alveolar macrophages and blood monocytes from controls released IL-1 (127 +/- 74.6 and 178.8 +/- 120 IL-1 units/ml, respectively) in the same amounts as AMs and blood monocytes from allergic asthmatics (148 +/- 47.5 and 160.5 +/- 78.3 IL-1 units/ml, respectively). After stimulation by anti-IgE or the specific allergen, asthmatic blood monocytes released IL-1-like activity (71.8 +/- 46.4 and 45.4 +/- 25.9 IL-1 units/ml, respectively). In contrast, asthmatic AM supernatants contained no detectable IL-1-like activity after stimulation by allergen or anti-IgE. The same pattern was observed with monocytes and AMs from controls after passive cell sensitization with 20% of IgE-rich serum. In a second step, the effect of supernatants of IgE-dependent stimulated AMs was tested on thymocyte proliferation induced by a purified IL-1, permitting the demonstration of an IL-1 inhibitory factor released by the AMs while these supernatants didn't modify the IL-2-dependent proliferation of a CTL-L line. The use of indomethacin and assessment of PGE2 levels in AM supernatants made it possible to discard the role of prostaglandins in this inhibitory effect. Moreover this activity, which is resistant to heat and trypsin treatment, has a molecular mass between 40 and 50 kD and did not correspond to serum proteases, alpha-1-antiproteinase, and arginase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Production of an interleukin-1 inhibitory factor by human alveolar macrophages from normals and allergic asthmatic patients. 326 76

Supernatants from PHA-activated human peripheral blood mononuclear cells, depleted of virtually all IL-2 activity by an anti-rIL-2 immunoadsorbent column, contain a factor(s) which synergizes with rIL-2 in facilitating the generation of allogeneic human CTL responses in vitro. This factor, provisionally termed CTL maturation factor (TcMF), did not appear to promote CTL responses in the absence of rIL-2. Furthermore, it acted later than IL-2 in facilitating CTL responses and could not be replaced by recombinant IFN-gamma. In this report we show that rIFN-alpha, rIL-1 alpha, and rIL-1 beta likewise lack TcMF activity. The TcMF activity in lymphokine-containing culture supernatants could be eliminated by trypsin or pronase but not by neuraminidase or RNase. Gel filtration revealed two peaks of TcMF activity, one at 12,000 to 25,000 Da and the other at 45,000 to 65,000 Da. Isoelectrofocusing demonstrated substantial charge heterogeneity. The majority of TcMF activity was recovered between pI 4.0 and pI 5.5 with a minor component at pI 6.5, corresponding to the areas in which IL-1 activity was also found. However, TcMF activity could be separated from IL-1 by reverse-phase HPLC. Moreover, TcMF recovered following reverse-phase HPLC was also found to be depleted of IL-4 activity. These studies suggest that TcMF activity is mediated by a protein(s) distinct from IL-1, IL-2, IL-4, and interferon-alpha or-gamma.
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PMID:Characterization of a factor(s) which synergizes with recombinant interleukin 2 in promoting allogeneic human cytolytic T-lymphocyte responses in vitro. 327 3


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