Dermatan sulfate activates nuclear factor-κb and induces endothelial and circulating intercellular adhesion molecule-1

Penc, Stanley F.; Pomahac, Bohdan; Eriksson, Elof; Detmar, Michael; Gallo, Richard L.

doi:10.1172/jci4742

Cited by 46 publications

(32 citation statements)

References 36 publications

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“…DISCUSSION Following injury, inflammation accompanies the wound healing process and is essential for defense against opportunistic pathogens, tissue repair, and remodeling. ECM components, (13,22). In the current study we demonstrate that HA becomes soluble after mechanical injury.…”

Section: Il-8 and Mip-2 Induction By Sha Is Tlr4-dependent-pat-supporting

confidence: 62%

Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4

Taylor

Trowbridge

Rudisill

et al. 2004

Journal of Biological Chemistry

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502

387

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Tissues must quickly recognize injury to respond to the rapid pace of microbial growth. In skin, dermal microvascular endothelial cells must also react to danger signals from the surrounding tissue and immediately participate by initiating the wound repair process. Components of the extracellular matrix such as hyaluronan are rapidly broken down into smaller molecular weight oligosaccharides in a wound, and these can activate a variety of biological processes. This study set out to determine if hyaluronan fragments released following injury can stimulate endothelial cells and what mechanism is responsible for this response. Using genechip microarray analysis, a response to hyaluronan fragments was detected in endothelial cells with the most significant increase observed for the chemokine IL-8. This observation was verified with qualitative reverse transcriptase-PCR and ELISA in human endothelial cell culture, and in a mouse model by observing serum levels of MIP-2 and KC following hyaluronan fragment administration in vivo. Activation was TLR4-dependent, as shown by use of TLR4 blocking antibody and TLR4-deficient mice, but not due to the presence of undetected contaminants as shown by inactivation following digestion with the hyaluronan-degrading enzyme chondroitinase ABC or incubation with the hyaluronan-specific blocking peptide Pep-1. Inactivation of LPS activity failed to diminish the action of hyaluronan fragments. These observations suggest that endogenous components of the extracellular matrix can stimulate endothelia to trigger recognition of injury in the initial stages of the wound defense and repair response.

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Section: Il-8 and Mip-2 Induction By Sha Is Tlr4-dependent-pat-supporting

confidence: 62%

Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4

Taylor

Trowbridge

Rudisill

et al. 2004

Journal of Biological Chemistry

Self Cite

502

387

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“…45 Thus, DS is the major soluble GAG present in human wound tissues, where its function includes promotion of the activity of FGF-2 46 and the activation of endothelial leukocyte adhesion through stimulation of ICAM-1. 47 Due to the restricted expression of EMR2/CD97 in myeloid and lymphoid cells, one can speculate that specific CS found in areas of tissue injury may have an important role in the recruitment of and the functional regulation of leukocytes expressing surface EMR2/CD97 during acute inflammation. CSPGs are also important during cholesterol deposition and foam-cell formation in atherogenesis.…”

Section: Discussionmentioning

confidence: 99%

The epidermal growth factor–like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans

Stacey

Chang

Davies

et al. 2003

Blood

195

218

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Using multivalent protein probes, an evolutionarily conserved endogenous ligand for EMR2, a human myeloid cell-restricted EGF-TM7 receptor, was identified on the surface of a number of adherent cell lines. In addition, in situ staining of the ligand has revealed specific in vivo patterns consistent with a connective tissue distribution. The interaction is conserved across species and mediated exclusively by the largest EMR2 isoform containing 5 epidermal growth factor (EGF)-like modules. Antibody-blocking studies subsequently revealed that the fourth EGF-like module constitutes the major ligandbinding site. The largest isoform of CD97, a related EGF-TM7 molecule containing an identical EGF-like module, also binds to the putative EMR2 ligand. Through the use of mutant Chinese hamster ovary (CHO) cell lines defective in glycosaminoglycans (GAGs) biosynthesis as well as the enzymatic removal of specific cell surface GAGs, the molecular identity of the EMR2 ligand was identified as chondroitin sulfate (CS). Thus, exogenous CS GAGs blocked the EMR2-ligand interaction in a dose-dependent manner. EMR2-CS interaction is Ca 2؉ -and sulphation-dependent and results in cell attachment. This is the first report of a GAG ligand for the TM7 receptors extending the already vast repertoire of stimuli of the GPCR superfamily.

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“…Culture Environment-The amount, relative CS composition, and sulfation pattern of CS influences cellular behaviors in response to GAGs produced during development, coagulation, and wound repair (7,(22)(23)(24). Therefore, we chose to characterize CS induced in fibroblasts switched from monolayer to 3D culture.…”

Section: Analysis Of Gags From Fibroblasts Switched To 3dmentioning

confidence: 99%

Dermatan Sulfate Proteoglycan and Glycosaminoglycan Synthesis Is Induced in Fibroblasts by Transfer to a Three-dimensional Extracellular Environment

Lee

Trowbridge

Taylor

et al. 2004

Journal of Biological Chemistry

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Composition and architecture of the extracellular matrix dictate cell behavior. Proteoglycans bind multiple components of the extracellular matrix by serving as important regulators of cell behavior. Given the influence of culture architecture on cell function, we investigated whether switching NIH3T3 fibroblasts from growth on type 1 collagen in monolayer to a collagen gel might influence dermatan sulfate expression. Immunofluorescent staining, immunoblot, and Western blot demonstrated an induction in decorin expression in cells switched to collagen gels. This induction was associated with a 40-fold increase in decorin transcript expression determined by quantitative real time PCR. Disaccharide analysis of extracted glycosaminoglycans from collagen gels showed an increase in total glycosaminoglycan and in the ratio of chondroitin sulfate to heparan sulfate compared with monolayer culture. The ratio of chondroitin sulfate to heparan sulfate likewise increased on syndecan-1 from gel culture. Digestion with chondroitinase B showed that this induced chondroitin sulfate was dermatan sulfate. Syndecan-1 extracted from wounded mouse skin also displayed an increase in dermatan sulfate synthesis compared with unwounded skin. Furthermore, glycosaminoglycans from collagen gel culture activated keratinocyte growth factor, whereas glycosaminoglycans from monolayer culture lacked this ability. These findings suggest that regulation of dermatan sulfate and dermatan sulfate proteoglycan is dependent on extracellular matrix architecture. The ability of collagen gel culture to mimic better the in vivo dermal environment may be due in part to this influence on dermatan sulfate and dermatan sulfate proteoglycan synthesis.Cell behavior is dependent on its environment. Extracellular matrix (ECM) 1 composition can dictate cell proliferation, movement, and morphology (1-3). Glycosaminoglycans (GAGs), such as heparan sulfate (HS) and chondroitin sulfate (CS), are important ECM components that can influence these cell behaviors. HS has been well described to be involved in a vast number of cell-cell and cell-matrix interactions ranging from processes such as development to microbial invasion (4 -6). A growing body of evidence has identified another GAG, CS-B or dermatan sulfate (DS), as playing a role in large number of similar cellular processes (7). The observation that DS is released at high concentrations during wound repair, and that it serves as a cofactor for several growth factors important to this process, has made it an attractive molecule for investigating cell-matrix interactions (8,9).DS is made up of repeating disaccharide units of iduronic acid and GalNAc and is the predominant GAG in the dermis (7, 10). The presence of GalNAc identifies DS as a chondroitin sulfate, whereas the presence of the iduronic acid sets DS apart from other chondroitin sulfates. DS and DS proteoglycans (DSPG) bind a long list of proteins influencing a large range of physiological processes. For example, binding of DS to heparin cofactor-II, thromb...

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Dermatan sulfate activates nuclear factor-κb and induces endothelial and circulating intercellular adhesion molecule-1

Cited by 46 publications

References 36 publications

Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4

Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4

The epidermal growth factor–like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans

Dermatan Sulfate Proteoglycan and Glycosaminoglycan Synthesis Is Induced in Fibroblasts by Transfer to a Three-dimensional Extracellular Environment

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