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PMID: 16873769 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TSG-6 potentiates the antitissue kallikrein activity of inter-alpha-inhibitor through bikunin release.

American journal of respiratory cell and molecular biology ·Vol. 36 ·No. 1 ·2007-01-00 ·Pages 20-31

Forteza R, Casalino-Matsuda SM, Monzon ME, Fries E, Rugg MS, Milner CM, Day AJ

Abstract

TSG-6 (the protein product of TNF-stimulated gene-6), an inflammation-associated protein, forms covalent complexes with heavy chains (HCs) from inter-alpha-inhibitor and pre-alpha-inhibitor and associates noncovalently with their common bikunin chain, potentiating the antiplasmin activity of this serine protease inhibitor. We show that TSG-6 and TSG-6.HC complexes are present in bronchoalveolar lavage fluid from patients with asthma and increase after allergen challenge. Immunodetection demonstrated elevated TSG-6 in the airway tissue and secretions of smokers. Experiments conducted in vitro with purified components revealed that bikunin.HC complexes (byproducts of TSG-6.HC formation) release bikunin. Immunoprecipitation revealed that bikunin accounts for a significant proportion of tissue kallikrein inhibition in bronchoalveolar lavage after allergen challenge but not in baseline conditions, confirming that bikunin in its free state, but not when associated with HCs, is a relevant protease inhibitor in airway secretions. In primary cultures of differentiated human airway epithelial and submucosal gland cells, TSG-6 is induced by TNF-alpha and IL-1beta, which suggests that these cells are responsible for TSG-6 release in vivo. Bikunin and HC3 (i.e., pre-alpha-inhibitor) were also induced by TNF-alpha in primary cultures. Our results suggest that TSG-6 may play an important protective role in bronchial epithelium by increasing the antiprotease screen on the airway lumen.

MeSH Terms
Adolescent Adult Alpha-Globulins/physiology Asthma/metabolism Bronchoalveolar Lavage Cell Adhesion Molecules/physiology Cells, Cultured Enzyme Activation Epithelial Cells/metabolism Exocrine Glands/cytology Female Humans Interleukin-1beta/physiology Male Membrane Glycoproteins/physiology Middle Aged Protein Binding Protein Subunits/metabolism Smoking/metabolism Tissue Kallikreins/physiology Tumor Necrosis Factor-alpha/physiology
Chemicals
Alpha-Globulins Cell Adhesion Molecules Interleukin-1beta Membrane Glycoproteins Protein Subunits SPINT2 protein, human TNFAIP6 protein, human Tumor Necrosis Factor-alpha inter-alpha-inhibitor Tissue Kallikreins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Forteza Rosanna
Division of Pulmonary and Critical Care Medicine (R-47), University of Miami School of Medicine, RMSB 7072A, Miami, FL 33136, USA. [email protected]
Casalino-Matsuda Susana M
Monzon Maria Elena
Fries Erik
Rugg Marilyn S
Milner Caroline M
Day Anthony J
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Article Info
Journal
American journal of respiratory cell and molecular biology
Abbr.
Am J Respir Cell Mol Biol
ISSN
1044-1549
DOI
10.1165/rcmb.2006-0018OC
Email
[email protected]
Published
2007-01-00
Epub
2006-00-27
Pages
20-31
Language
English
Region
United States
NLM ID
8917225
PMCID
PMC1899306
Subset
IM
Grants
NHLBI NIH HHS · HL-073156 · United States
NHLBI NIH HHS · HL-68992 · United States
External Links
PubMed source DOI: 10.1165/rcmb.2006-0018OC PMC Full Text View journal details
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