Home About Browse Search

Biological functions and regulation of serglycin-dependent mast cell proteases

Lundequist, Anders (2006). Biological functions and regulation of serglycin-dependent mast cell proteases. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis Agriculturae Sueciae, 1652-6880 ; 2006:10
ISBN 91-576-7059-5
[Doctoral thesis]

[img] PDF


Mast cells (MCs) are immune cells that release preformed mediators from granules when activated by e.g. bacteria, viruses and allergens. Among the granule components are proteoglycans, histamine and proteases (chymase, tryptase and carboxypeptidase A). The proteases are bound to serglycin proteoglycans in the granules, and some remain attached to the proteoglycans after expulsion from the secretory granules. The importance of the interaction between proteases and proteoglycans is exemplified by MCs lacking an enzyme essential for heparin biosynthesis, N-deactylase/Nsulfotransferase-2 (NDST-2). Mice with this deficit display impaired storage of many MC granule components, e.g. proteases and histamine. We could show that polycationic compounds inhibited chymase (mMCP-4/rMCP-1) by disrupting its interaction with heparin. Furthermore, these polycations inhibited human tryptase (recombinant βI-tryptase) and made the otherwise resilient enzyme susceptible to macromolecular inhibitors. Our findings may be of therapeutic interest when treating pathologies associated with these enzymes. Mast cells may take part in regulation of blood pressure and angiogenesis, and this could occur through metabolism of the peptide angiotensin I (AngI). We confirmed the MC involvement in AngI processing using the NDST-2 deficient mice. We subsequently elucidated that the responsible proteases were chymase (mMCP-4) and carboxypeptidase A (CPA), and that they acted in concert on AngI, producing both blood pressure elevating peptides and blood pressure reducing peptides. Mast cells are implicated in connective tissue regulation, and a suggested pathway is through activation of matrix degrading enzymes, e.g. the matrix metalloproteases (MMPs). We could show that activation of proMMP-9 is dependent on MCs, and especially the chymase mMCP-4, as shown by impaired processing of proMMP-9 in peritoneal cell cultures from mice lacking NDST-2 or mMCP-4. Investigation of tissues from mMCP-4-/- revealed increased deposits of extracellular matrix components and reduced levels MMP-9. Additionally, we could show that proMMP-2 processing was completely abolished in peritoneal cell cultures from mice lacking serglycin. Furthermore, we showed that the formation of MMP-2 was abrogated in the presence of serine protease inhibitors and when cell cultures were depleted of MCs. The latter study reveals a novel pathway for proMMP-2 processing, which could be of relevance in connection with MMP2-associated pathological conditions such as cancer.

Authors/Creators:Lundequist, Anders
Title:Biological functions and regulation of serglycin-dependent mast cell proteases
Series Name/Journal:Acta Universitatis Agriculturae Sueciae
Year of publishing :February 2006
Number of Pages:54
ALLI. Lundequist, A., Juliano, M.A., Juliano, J., Pejler, G., “Polycationic peptides as inhibitors of mast cell serine proteases”, Biochemical Pharmacology (2003), 65:1171-80 II. Lundequist, A.Tchougounova, E., Åbrink, M., Pejler, G. “Cooperation between Mast Cell Carboxypeptidase A and the Chymase Mouse Mast Cell 4 in the Formation and Degradation of Angiotensin II”, The Journal of Biological Chemistry (2004), 279 (31): 32339-44 III. Tchougounova, E., Lundequist, A., Fajardo, I., Winberg, J-O.,Åbrink, M., Pejler, G., “A Key Role for Mast Cell Chymase in the Activation of Promatrix Metalloprotease-9 and Pro-matrix Metalloprotease-2”, The Journal of Biological Chemistry (2005), 280 (10):9291-96 IV. Lundequist, A., Åbrink, M., Pejler, G., “Mast Cell-dependent Activation of Pro-matrix Metalloprotease-2: A Role for Serglycin proteoglycandependent Mast Cell Proteases”, Submitted Papers I-III are reproduced by kind permission of the journals concerned.
Place of Publication:Uppsala
ISBN for printed version:91-576-7059-5
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, proteases, granules, proteoglycans, histamine, allergens, arthritis, neoplasms, analytical methods
Keywords:mast cell mediator, protease, chymase, matrix metalloprotease, proteoglycan, allergy, arthritis, cancer
Permanent URL:
ID Code:1036
Department:(VH) > Dept. of Molecular Biosciences (until 070101)
Deposited By: Anders Lundequist
Deposited On:17 Feb 2006 00:00
Metadata Last Modified:02 Dec 2014 10:09

Repository Staff Only: item control page


Downloads per year (since September 2012)

View more statistics