Disease relevance of Ctsg

• Although cathepsin G has previously shown to have broad spectrum antibiotic properties, challenges of mice with Staphylococcus aureus, Klebsiella pneumoniae, or Escherichia coli yielded survivals that were not different from those of wild-type animals [1].
• The data demonstrate a critical role of the nonoxidative effector mechanisms of neutrophils in host immunity and immunopathology and identify elastase and cathepsin G as effectors in the endotoxic shock cascade downstream of TNFalpha [2].
• Transgenic mice expressing PML-RARalpha in early myeloid cells under control of human cathepsin G regulatory sequences all develop a myeloproliferative syndrome, but only 15% to 20% develop acute promyelocytic leukemia (APL) after a latent period of 6 to 14 months [3].
• Finally, the PAI-1 mutants were more effective in reducing the neutrophil elastase and cathepsin G activities in an in vivo model of lung inflammation than were their physiological inhibitors [4].
• Cathepsin-G Interferes with Clearance of Pseudomonas aeruginosa from Mouse Lungs [5].

High impact information on Ctsg

• Serine protease cathepsin G regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering [6].
• Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G [2].
• We examined the role of leukocytic neutral proteinases by comparing the glomerular damage and albuminuria after injection of rabbit anti-mouse GBM antibodies in normal control mice (C57BL/6J, +/+) and in beige mice (C57BL/6J,bg/bg) in which PMN are deficient of the neutral proteinases elastase and cathepsin G [7].
• Elicited peritoneal neutrophils of beige (Chediak-Higashi) mice essentially lack activities of the neutral serine proteinases elastase and cathepsin G, which may explain the increased susceptibility to infection of beige mice and Chediak-Higashi patients [8].
• The results of several experiments indicate that neutrophils were the sole source of elastase and cathepsin G in bone marrow [8].

Chemical compound and disease context of Ctsg

• Using a murine model of endobronchial inflammation, we found that a different neutrophil-derived serine protease, cathepsin G, inhibited the host's ability to clear Pseudomonas from the lung, based on a 1-log reduction in bacteria recovered from cathepsin G-deficient mice [5].

Biological context of Ctsg

• Hematopoiesis in cathepsin G-/- mice is normal, and the mice have no overt abnormalities in blood clotting [1].
• Neutrophils derived from cathepsin G-/- mice have normal morphology and azurophil granule composition; these neutrophils also display normal phagocytosis and superoxide production and have normal chemotactic responses to C5a, fMLP, and interleukin-8 [1].
• In contrast, a targeted mutation of the promyelocyte-specific cathepsin G gene (which lies just 3' to the granzyme genes in the same cluster) had minimal effects on upstream granzyme gene expression [9].
• Because the transgene includes only 6 kb of regulatory sequences from the human cathepsin G locus, we hypothesized that sequences required for high-level expression of the transgene might be located elsewhere in the cathepsin G locus and that a knock-in model might yield much higher expression levels and higher penetrance of disease [3].
• 2. Although the murine orthologue of human granzyme H has not yet been identified, murine granzymes C, D, E, F, and G also lie between the murine granzyme B and cathepsin G genes on murine chromosome 14; murine granzymes C, D, and F are also highly expressed in LAK cells, but minimally in cytotoxic T lymphocytes (CTL) [10].

Anatomical context of Ctsg

• Normal neutrophil function in cathepsin G-deficient mice [1].
• Bone marrow derived from mice homozygous for this mutation had no detectable cathepsin G protein or activity, indicating that no other protease in bone marrow cells has the same specificity [1].
• Cathepsin G is a neutral serine protease that is highly expressed at the promyelocyte stage of myeloid development [1].
• We, therefore, targeted a human PML-RARalpha cDNA to the 5' untranslated region of the murine cathepsin G gene, using homologous recombination in embryonic stem cells [3].
• Expression of cathepsin G-like and alpha 1-antichymotrypsin-like proteins in reactive astrocytes [11].

Associations of Ctsg with chemical compounds

• This protective effect correlates with the inactivation of neutrophil-derived serine proteases, since NE(-/-) x CG(-/-) mice are equally resistant to arthritis induction by anti-collagen antibodies [12].
• Cartilage proteoglycan depletion was quantified by measuring the decrease in safranin O staining intensity, and this, too, was unaltered in mice lacking elastase and cathepsin G [13].
• Elastase and cathepsin G activities were assayed with the specific synthetic substrates MeO-Suc-Ala-Ala-Pro-Val-MCA and Suc-Ala-Ala-Pro-Phe-pNA, respectively [14].
• Complex formation is maximal at a 1:1 molar ratio of cathepsin G to alpha 1-antichymotrypsin (alpha 1-ACT) as revealed by sodium dodecyl sulfate-gel electrophoresis and autoradiography [15].
• Injection of cathepsin G in BALB/c mice immunized with keyhole limpet hemocyanin (KLH) adsorbed to aluminum hydroxide resulted in a significantly increased production of KLH-specific IgG1 and IgG2a antibodies [16].

Other interactions of Ctsg

• Characterization of cDNA clones encoding mouse proteinase 3 (myeloblastine) and cathepsin G [17].
• We also showed the deficient expression of granzyme B and cathepsin G genes in mi/mi CMC [18].
• We demonstrate that these values are a consequence of a decreased concentration of the alpha 1-protease inhibitor for elastase [PI(E)], which is the major serum inhibitor of elastase and cathepsin G [19].
• The other fish SPs identified are termed 'Gzm-like' and are distantly related to a large heterogeneous group of hematopoietic SPs, including most of the T-cell Gzms (B-H), the mast cell chymases, the mast cell/basophil proteases of the mouse mast cell protease-8 subfamily (M8-family) and the neutrophil cathepsin G [20].
• Neutrophil elastase, chymase (mouse mast cell protease-1, mMCP-1), and cathepsin G were also inhibited by TsCEI, whereas trypsin, thrombin, and factor Xa were not [21].

Analytical, diagnostic and therapeutic context of Ctsg

• Using a polymerase chain reaction (PCR)-based strategy for the isolation of trypsin-related serine proteases, we were able to isolate cDNAs for two of the major neutrophil and monocyte serine proteases in the mouse, cathepsin G and mouse protease 3 (myeloblastin) [17].
• Molecular cloning, chromosomal location, and tissue-specific expression of the murine cathepsin G gene [22].
• The 5' end of the cathepsin G gene was defined by primer extension and S1 nuclease protection assays [23].
• Using in situ hybridization techniques, we localized cathepsin G to chromosome 14q11.2, a site that is near the alpha/delta T-cell receptor complex [23].
• Cathepsin G activity in the cell-free supernatant of peritoneal lavage fluid was normal; elastolytic activity was initially very low but increased to about twice baseline level after 4 h at 25 degrees C and to about 20-fold at 36 h [24].

References