Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of Bestatin, a low molecular weight metabolite of Streptomyces olivoreticuli on the human and mouse/rat immune system, have been studied in detail. To describe the activity of the immunomodulating dipeptide, it has been tested in vitro, ex vivo and in vivo in various experimental models. Bestatin simultaneously applied with selected antigens to mice was able to enhance the DTH response against a challenge injection of the respective antigen given into the footpad. Serum antibody levels against those antigens were uneffected. However, an increase of PFC could be found in those mice given high doses of Bestatin. On natural killer cell activity against Yac-1 tumor cells the dipeptide had no effect in low responder (DBA2/J) mice. In high responder mice (CBA/JCr), however, a significant increase of NK cell activity of spleen cells could be found, when the drug was given on day 0 or on days 0 to 3 and the test was performed on day 4. Bestatin had no effect on the generation of allogeneic cytotoxic T-lymphocytes in vivo or in vitro and even a suppressive effect on the induction of syngeneic antitumor CTL. Contrary to this suppressive effect, Bestatin increases in the popliteal lymph node assay the weights in a dose-dependent way. When mouse macrophages or human monocytes were either incubated in vitro with Bestatin or mice were treated with the dipeptide parenterally or orally and the macrophages from those mice were investigated, Bestatin induced in vitro and in vivo a dose-dependent increase in pinocytic uptake of radioactive colloidal gold. Also the oxidative metabolism was dose-dependently augmented as measured by chemiluminescence. Bestatin modulates the macrophage mediated cytotoxicity. In vitro or in vivo activated mononuclear phagocytes exhibited a dose-dependent increase in cytotoxic activity for several tumor target cells. A minimum ratio of 50:1 effector to target cells was necessary for this cytotoxic effect. A similar degree of activation was observed in macrophages from athymic nu/nu-mice or from endotoxin resistant C3H/HeJ-mice. Other parameters of macrophage activation were determined by measuring secretion of lysosomal enzymes and liberation of prostaglandins. Bestatin interacts with macrophages in vivo and in vitro by increasing their secretory activity of acid hydrolases (beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-D-glucosaminidase). This release was dose- and time-dependent and not associated with any sign of cell death. Another class of mediators produced by macrophages after stimulation with Bestatin were the prostaglandins E2 and F2a.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies on the mechanisms of action of the immunomodulator Bestatin in various screening test systems. 638 22

Rat natural killer cell Met-ase-1 (RNK-Met-1) is a 30,000 M(r) serine protease (granzyme) found in the cytolytic granules of CD3- large granular lymphocytes (LGL) with natural killer (NK) activity. To characterize the genomic sequences responsible for the CD3- LGL-restricted expression of this gene, we screened a rat genomic library with RNK-Met-1 cDNA, and obtained bacteriophage clones that contained the RNK-Met-1 gene. The RNK-Met-1 gene comprises 5 exons and spans approximately 5.2 kilobases (kb), exhibiting a similar structural organization to a class of CTL-serine proteases with protease catalytic residues encoded near the borders of exons 2, 3, and 5. The 5'-flanking region of the RNK-Met-1 gene contains a number of putative promoter and enhancer regulatory elements and shares several regions of homology with the 5'-flanking region of the mouse perforin gene. We have prepared nested deletions from approximately 3.3 kb of the 5'-flanking region of the RNK-Met-1 gene, and inserted these upstream of the chloramphenicol acetyltransferase (CAT) reporter gene. These 5'-flanking RNK-Met-1-CAT constructs were transiently transfected into rat LGL leukemia, T-lymphoma, and basophilic leukemia cell lines. The transcriptional activity of the RNK-Met-1 5'-flanking region was strong, restricted to the RNK-16 LGL leukemia and controlled by several positive cis-acting regions spread over at least 3.3 kb. The longest and most active 5'-flanking region (-3341 to -33) was also used to drive specific expression of beta-galactosidase in RNK-16. These data are consistent with the NK cell-specific expression of RNK-Met-1 and suggest the potential utility of this gene promoter in the development of transgene models of NK cell biology in vivo.
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PMID:Cloning and characterization of a novel NK cell-specific serine protease gene and its functional 5'-flanking sequences. 760 1

Interleukin-10 (IL-10) has a wide range of in vivo biological activities and is a key regulatory cytokine of immune-mediated inflammation. The authors found that murine IL-10 given 12 hours after a recombinant vaccinia virus (rVV) containing the LacZ gene significantly enhanced the treatment of mice bearing 3-day-old pulmonary metastases expressing beta-galactosidase. Because IL-10 has been shown to inhibit the functions of key elements of both innate and acquired immune responses, the authors hypothesized that IL-10 might act by inhibiting clearance of the rVV, thus prolonging exposure to the experimental antigen. However, evidence that IL-10 was not acting primarily through such negative regulatory mechanisms included the following: (a) IL-10 also enhanced the therapeutic effectiveness of a recombinant fowlpox virus, which cannot replicate in mammalian cells; (b) Titers of rVV in immunized mice were lower, not higher; and (c) Although IL-10 did not alter levels of anti-vaccinia anti-bodies or natural killer cell activity, rVV-primed mice treated with IL-10 had enhanced vaccinia-specific cytotoxic T-lymphocyte activity. Thus, IL-10 enhanced the function of a recombinant poxvirus-based anti-cancer vaccine and may represent a potential adjuvant in the vaccination against human cancers using recombinant poxvirus-based vaccines.
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PMID:Interleukin-10 enhances the therapeutic effectiveness of a recombinant poxvirus-based vaccine in an experimental murine tumor model. 1057 Jul 47

We investigated the efficacy of intratumoral injection of macrophages transduced with murine IL-12 recombinant adenoviral vector (AdmIL-12) using the orthotopic 178-2 BMA mouse prostate cancer model. AdmIL-12-transduced macrophages secreted IL-12 in vitro and demonstrated increased surface expression of MHC classes I and II as well as F4/80 antigen compared with uninfected macrophages or those infected with an adenoviral vector containing beta-galactosidase (Adbetagal) in control macrophages. AdmIL-12-transduced macrophages injected into orthotopic 178-2 BMA tumors in vivo induced significant suppression of primary tumor growth and spontaneous lung metastases compared with controls. These antitumor and antimetastatic effects were comparable with those resulting from direct orthotopic delivery of the AdmIL-12 vector. Mice with orthotopic tumors treated with AdmIL-12-transduced macrophages survived significantly longer than controls. Analysis of tumors demonstrated significantly increased infiltration of CD4+ and CD8+ T cells in those injected with AdmIL-12-transduced macrophages compared with controls. Splenocyte-derived cytotoxic natural killer cell activity was enhanced on day 2 after AdmIL-12-transduced macrophage injection, and on day 14, tumor-specific T-lymphocyte activities were increased compared with control, Adbetagal-infected macrophages. Trafficking studies confirmed that intratumorally injected, AdmIL-12-transduced macrophages could migrate to draining lymph nodes. Overall, this novel approach to prostate cancer therapy demonstrates antitumor immune responses that provide effective antimetastatic activities in preclinical studies.
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PMID:Macrophages transduced with an adenoviral vector expressing interleukin 12 suppress tumor growth and metastasis in a preclinical metastatic prostate cancer model. 1463 13

After intravenous injection of replication-deficient adenovirus, hepatocytes are transduced and express high levels of adenovirus-encoded genes. However, adenovirally encoded gene expression is ablated rapidly by CD8+ T-cell-dependent mechanisms. Thus, this model is suitable for examining intrahepatic cytotoxic T lymphocyte (CTL) effector mechanisms. In the present studies, recombinant adenoviruses encoding secreted (human apolipoprotein A-I) or intracellular (beta-galactosidase) gene products were infused into mice with genetic deficiencies affecting the granule exocytosis-, Fas-, or tumor necrosis factor receptor 1 (TNFR1)-mediated pathways of CTL and natural killer cell effector function; the rates of clearance of adenovirus-encoded gene products were assessed. Clearance of secreted or intracellular adenoviral gene products was not delayed in perforin-deficient mice or dipeptidyl peptidase I-deficient mice, which fail to process and activate granzyme A or granzyme B. TNFR1-deficient mice also exhibited no delay in clearance of adenoviral gene products. However, adenoviral clearance from Fas-deficient mice was delayed, and such delays were much greater in mice deficient in both TNFR1 and Fas. In contrast, chimeric mice lacking both hepatic Fas and lymphocyte perforin function exhibited no greater delay in adenoviral clearance than chimeras deficient only in hepatic Fas expression. In conclusion, Fas-dependent mechanisms are required for efficient clearance of virally infected hepatocytes and, in Fas-deficient animals, TNFR1-dependent mechanisms provide an alternative mechanism for hepatic adenovirus clearance. In contrast, perforin- and granule protease-dependent cytotoxicity mechanisms play no apparent role in clearance of adenovirus from the liver.
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PMID:Fas and TNFR1, but not cytolytic granule-dependent mechanisms, mediate clearance of murine liver adenoviral infection. 1561 34