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Biological function of mast cell chymase

in vitro and in vivo studies: a thorny pathway

Chugunova, Elena (2004). Biological function of mast cell chymase. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae. Veterinaria, 1401-6257 ; 181
ISBN 91-576-6680-6
[Doctoral thesis]

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Abstract

Mast cells (MCs) are key effector cells in various types of inflammatory conditions. The MC secretory granules contain inflammatory mediators such as histamine, heparin proteoglycan (PG), cytokines and various heparin-binding proteases, including tryptases, chymases and carboxypeptidase A. Previously, a mouse strain with a defect in its heparin biosynthesis was produced by targeting the gene for NDST-2 (N-deacetylase/N-sulfotransferase-2). These mice showed reduced levels of MC inflammatory mediators such as histamine and various heparin-binding proteases, including chymases, tryptases, and carboxypeptidase A. By using this mouse strain, we found that chymase in complex with heparin PG degraded fibronectin, suggesting a role for chymase in the regulation of connective tissue composition. Further, we found that chymase/heparin PG complexes degraded and thereby inactivated both thrombin and plasmin, suggesting an additional role for chymase in regulation of extravascular coagulation and fibrinolysis. However, although our findings implicated chymase in these processes, it was not possible to exclude the contribution to the observed activities by other MC components that are influenced by the knockout of NDST-2. Out of the different mouse chymases, mouse MC protease 4 (mMCP-4) has the most similar tissue distribution, heparin-binding and angiotensin I-converting properties as the only identified human chymase. Thus, mMCP-4 may be the closest homologue to human chymase and we therefore chose to target the gene for mMCP-4. A mouse strain with a targeted inactivation of the mMCP-4 gene was generated. This mouse strain displayed defects in the regulation of thrombin and in fibronectin turnover, demonstrating a key role for mMCP-4 in these processes. To address the role of MC proteases in the activation of matrix metalloproteases (MMPs) we used both the NDST-2 and mMCP-4 deficient mice. An analysis of peritoneal cells and tissue extracts from these mice revealed the presence of both pro-MMP-9 and active enzyme (MMP-9) in WT mice, but only the proform of MMP-9 was found in knockout mice. We also found that mMCP-4 can regulate the activation of pro-MMP-2 in the same manner. Our findings suggest that mMCP-4 plays a critical role in the activation of both pro-MMP-2 and pro-MMP-9 in vivo. The mMCP-4 knockout led to the accumulation of the fibronectin and collagen, resulting in fibrotic signs in the skin of the mMCP-4-/- mice. Possibly, mMCP-4-mediated activation of pro-MMP-2 and -9 may provide a link between MCs and processes that are regulated by MMPs.

Authors/Creators:Chugunova, Elena
Title:Biological function of mast cell chymase
Subtitle:in vitro and in vivo studies: a thorny pathway
Year of publishing :January 2004
Volume:181
Number of Pages:51
Papers/manuscripts:
NumberReferences
ALLI. Tchougounova, E., Forsberg, E., Angelborg, G., Kjellen, L., Pejler, G. (2001) Altered processing of fibronectin in mice lacking heparin. A role for heparin-dependent mast cell chymase in fibronectin degradation. J. Biol. Chem. 276, 3772-3777 II. Tchougounova, E. & Pejler, G. (2001) Regulation of extravascular coagulation and fibrinolysis by heparin-dependent mast cell chymase. FASEB J. 15, 2763-2765 III. Tchougounova, E., Pejler, G. & Åbrink, M. (2003) The chymase, mouse mast cell protease 4, constitutes the major chymotrypsin-like activity in peritoneum and ear tissue. A role for mouse mast cell protease 4 in thrombin regulation and fibronectin turnover. J. Exp. Med. 198, 423-431 IV. Tchougounova, E., Lundequist, A., Fajardo, I., Winberg, J.-O., Åbrink, M. & Pejler, G. A key role for the mast cell chymase, mouse mast cell protease 4, in the activation of pro-matrix metalloprotease-9 and -2 in vivo. (Manuscript).
Place of Publication:Uppsala
ISBN for printed version:91-576-6680-6
ISSN:1401-6257
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X30 Life sciences
Subjects:Not in use, please see Agris categories
Agrovoc terms:mast cells
Keywords:mast cell, serine protease, chymase, heparin, N-deacetylase/ N-sulfotransferase, fibronectin, thrombin, matrix metalloproteinase
URN:NBN:urn:nbn:se:slu:epsilon-464
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-464
ID Code:723
Department:(VH) > Dept. of Molecular Biosciences (until 070101)
Deposited By: Elena Chugunova
Deposited On:10 Jan 2005 00:00
Metadata Last Modified:02 Dec 2014 10:06

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