Inter-α-trypsin Inhibitor, a Covalent Protein-Glycosaminoglycan-Protein Complex

Zhuo, Lisheng; Hascall, Vincent C.; Kimata, Koji

doi:10.1074/jbc.r300039200

Cited by 210 publications

(219 citation statements)

References 74 publications

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“…5A). IaI consists of two heavy chains, which can bind hyaluronan, and a light chain called urinary trypsin inhibitor/bikunin, which is an anti-inflammatory protease inhibitor, but does not bind hyaluronan (20). We therefore tested whether the hyaluronan-binding component of IaI was necessary to mediate ozone-induced AHR.…”

Section: Ha Recognition Is Required For the Development Of Ahr Aftermentioning

confidence: 99%

Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice

Garantziotis

Potts

et al. 2009

Journal of Biological Chemistry

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113

136

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Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced bronchoconstriction, remain poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that hyaluronan contributes to airway hyperreactivity (AHR) after exposure to ambient ozone. Using an established model of ozone-induced airways disease, we characterized the role of hyaluronan in airway hyperresponsiveness. The role of hyaluronan in response to ozone was determined by using therapeutic blockade, genetically modified animals, and direct challenge to hyaluronan. Ozone-exposed mice demonstrate enhanced AHR associated with elevated hyaluronan levels in the lavage fluid. Mice deficient in either CD44 (the major receptor for hyaluronan) or inter-␣-trypsin inhibitor (molecule that facilitates hyaluronan binding) show similar elevations in hyaluronan but are protected from ozone-induced AHR. Mice pretreated with hyaluronan-binding peptide are protected from the development of ozone-induced AHR. Overexpression of hyaluronan enhances the airway response to ozone. Intratracheal instillation of endotoxin-free low molecular weight hyaluronan induces AHR dependent on CD44, whereas instillation of high molecular weight hyaluronan protects against ozone-induced AHR. In conclusion, we demonstrate that hyaluronan mediates ozoneinduced AHR, which is dependent on the fragment size and both CD44 and inter-␣-trypsin inhibitor. These data support the conclusion that pulmonary matrix can contribute to the development of airway hyperresponsiveness.Ozone is a commonly encountered urban air pollutant that significantly contributes to increased morbidity (1-4) and can lead to a significant economic burden. It has been estimated that each year inhalation of ambient ozone contributes to 800 premature deaths, 4,500 hospital admissions, 900,000 school absences, and more than 1 million restricted activity days with an estimated $5 billion annual economic burden (5). Population-based studies suggest that for each 10 ppb increase in 1-h daily maximum level of ozone there is an increase in mortality risk of 0.39 -0.87%, especially in individuals with pre-existing respiratory disease (2, 3, 6, 7). However, the biological mechanisms, which regulate the response to ambient ozone exposure, remain poorly understood.Hyaluronan is an abundant extracellular matrix component, which has been recently shown to play a significant role in the response to noninfectious lung injury. Short fragment hyaluronan (sHA) 2 is released in the lung after sterile injury such as bleomycin instillation (8) or high tidal volume ventilation (9) and can modify the tissue response to injury. Furthermore, hyaluronan has been identified in airway secretions from asthmatics (10), and high molecular weight hyaluronan can attenuate the bronchoconstrictive response in exercise-induced asthma (11). We therefore hypothesized that...

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Section: Ha Recognition Is Required For the Development Of Ahr Aftermentioning

confidence: 99%

Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice

Garantziotis

Potts

et al. 2009

Journal of Biological Chemistry

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113

136

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“…Earlier, inter-␣-inhibitor (I␣I), a normal plasma protein, was shown to form stable complexes with TSG-6 and HA (26,29,(32)(33)(34). I␣I consists of three polypeptide chains, two so-called heavy chains and bikunin, that are linked by a C-4-S chain, resulting in a protein-GAG-protein bridge (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

TSG-6 Protein Binding to Glycosaminoglycans

Wisniewski

Snitkin

Mindrescu

et al. 2005

Journal of Biological Chemistry

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TSG-6 protein, up-regulated in inflammatory lesions and in the ovary during ovulation, shows anti-inflammatory activity and plays an essential role in female fertility. Studies in murine models of acute inflammation and experimental arthritis demonstrated that TSG-6 has a strong anti-inflammatory and chondroprotective effect. TSG-6 protein is composed of the N-terminal link module that binds hyaluronan and a C-terminal CUB domain, present in a variety of proteins. Interactions between the isolated link module and hyaluronan have been studied extensively, but little is known about the binding of full-length TSG-6 protein to hyaluronan and other glycosaminoglycans. We show that TSG-6 protein and hyaluronan, in a temperature-dependent fashion, form a stable complex that is resistant to dissociating agents. The formation of such stable complexes may underlie the activities of TSG-6 protein in inflammation and fertility, e.g. the TSG-6-dependent cross-linking of hyaluronan in the cumulus cell-oocyte complex during ovulation. Because adhesion to hyaluronan is involved in cell trafficking in inflammatory processes, we also studied the effect of TSG-6 on cell adhesion. TSG-6 binding to immobilized hyaluronan did not interfere with subsequent adhesion of lymphoid cells. In addition to immobilized hyaluronan, full-length TSG-6 also binds free hyaluronan and all chondroitin sulfate isoforms under physiological conditions. These interactions may contribute to the localization of TSG-6 in cartilage and to its chondroprotective and anti-inflammatory effects in models of arthritis.

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“…For example, the Cterminal lectin-like domain of versican has been shown to bind to multimeric tenascin-R and tenascin-C in a calcium-dependent manner, creating the possibility of crosslinking hyaluronan through non-covalent versican-tenascin-versican interactions [33,34]. Other studies have implicated inter-alpha trypsin inhibitor (IαI) as necessary for the formation of cell coats [35,36], for the maintenance of hyaluronan scaffold integrity during cumulus expansion [37], and for potentiating CD44-mediated leukocyte adhesion to hyaluronan-rich matrices [38,39]. IαI heavy chains are transferred from the chondroitin sulfate chain of IαI to the hyaluronan.…”

Section: Hyaluronan Crosslinkingmentioning

confidence: 99%

Hyaluronan-dependent pericellular matrix☆

Evanko¹,

Tammi²,

Tammi³

et al. 2007

Advanced Drug Delivery Reviews

257

238

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Hyaluronan is a multifunctional glycosaminoglycan that forms the structural basis of the pericellular matrix. Hyaluronan is extruded directly through the plasma membrane by one of three hyaluronan synthases and anchored to the cell surface by the synthase or cell surface receptors such as CD44 or RHAMM. Aggregating proteoglycans and other hyaluronan-binding proteins, contribute to the material and biological properties of the matrix and regulate cell and tissue function. The pericellular matrix plays multiple complex roles in cell adhesion/de-adhesion, and cell shape changes associated with proliferation and locomotion. Time-lapse studies show that pericellular matrix formation facilitates cell detachment and mitotic cell rounding. Hyaluronan crosslinking occurs through various proteins, such as tenascin, TSG-6, inter-alpha-trypsin inhibitor, pentraxin and TSP-1. This creates higher order levels of structured hyaluronan that may regulate inflammation and other biological processes. Microvillous or filopodial membrane protrusions are created by active hyaluronan synthesis, and form the scaffold of hyaluronan coats in certain cells. The importance of the pericellular matrix in cellular mechanotransduction and the response to mechanical strain are also discussed.

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Inter-α-trypsin Inhibitor, a Covalent Protein-Glycosaminoglycan-Protein Complex

Cited by 210 publications

References 74 publications

Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice

Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice

TSG-6 Protein Binding to Glycosaminoglycans

Hyaluronan-dependent pericellular matrix☆

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