The Role of Up-Regulated Serine Proteases and Matrix Metalloproteinases in the Pathogenesis of a Murine Model of Colitis

Tarlton, John F; Whiting, Christine V.; Tunmore, David; Bregenholt, Søren; Reimann, Jörg; Claësson, Mogens H.; Bland, Paul W.

doi:10.1016/s0002-9440(10)64831-6

Cited by 94 publications

(71 citation statements)

References 32 publications

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“…Protein analysis using ExPASy demonstrated that MD-2 contained multiple trypsin cleavage sites. High amounts of proteolytically active trypsin have recently been found predominantly at mucosal sites of acute inflammation in the small intestine (24,38,39). As confirmed by immunofluorescence microscopy, trypsin content was significantly increased in severely inflamed areas of ileal mucosa in active CD ileitis, whereas colitic samples of UC or CD patients exhibited negligible amounts of trypsin (Fig.…”

Section: Trypsin-induced Proteolytic Digestion Of Md-2 Multimer Desenmentioning

confidence: 65%

“…IEC of noninvolved areas close to ileal inflammation were positive for MD-2 in CD, suggesting that translational synthesis is not primarily disturbed and that reduction may rather reflect the secondary effect of some inflammatory mediator(s) present in active ileitis. Proteolytically active trypsin is known to be increased in acute mucosal inflammation of the small intestine and proximal colon (24,38,39). Decreased MD-2 correlated inversely with augmented trypsin activity in CD-associated ileal areas of severe inflammation, and increased MD-2 was associated with diminished trypsin expression in colonic areas of mucosal inflammation in CD or UC patients.…”

Section: Discussionmentioning

confidence: 95%

“…The serine protease trypsin has previously been implicated in tissue destruction in acute small intestinal inflammation (23,24). However, by acting as prodefensin convertase in Paneth cells, trypsin is also involved as host defense mechanism in the regulation of innate immunity in the small intestine (25).…”

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confidence: 99%

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Trypsin-Sensitive Modulation of Intestinal Epithelial MD-2 as Mechanism of Lipopolysaccharide Tolerance

Cario

Golenbock

Visintin

et al. 2006

The Journal of Immunology

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Intestinal epithelial cells (IEC) are constantly exposed to both high concentrations of the bacterial ligand LPS and the serine protease trypsin. MD-2, which contains multiple trypsin cleavage sites, is an essential accessory glycoprotein required for LPS recognition and signaling through TLR4. The aim of this study was to characterize the expression and subcellular distribution of intestinal epithelial MD-2 and to delineate potential functional interactions with trypsin and then alteration in inflammatory bowel disease (IBD). Although MD-2 protein expression was minimal in primary IEC of normal colonic or ileal mucosa, expression was significantly increased in IEC from patients with active IBD colitis, but not in ileal areas from patients with severe Crohn’s disease. Endogenous MD-2 was predominantly retained in the calnexin-calreticulin cycle of the endoplasmic reticulum; only a small fraction was exported to the Golgi. MD-2 expression correlated inversely with trypsin activity. Biochemical evidence and in vitro experiments demonstrated that trypsin exposure resulted in extensive proteolysis of endogenous and soluble MD-2 protein, but not of TLR4 in IEC, and was associated with desensitization of IEC to LPS. In conclusion, the present study suggests that endoplasmic reticulum-associated MD-2 expression in IBD may be altered by ileal protease in inflammation, leading to impaired LPS recognition and hyporesponsiveness through MD-2 proteolysis in IEC, thus implying a physiologic mechanism that helps maintain LPS tolerance in the intestine.

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Section: Trypsin-induced Proteolytic Digestion Of Md-2 Multimer Desenmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Trypsin-Sensitive Modulation of Intestinal Epithelial MD-2 as Mechanism of Lipopolysaccharide Tolerance

Cario

Golenbock

Visintin

et al. 2006

The Journal of Immunology

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“…Our laboratory has also shown that such MMP9 driven inflammation was largely mediated by MMP9 expressed by epithelial cells in response to the inflammatory challenge (12). Furthermore, MMP9 activity is correlated with active inflammation associated with fistula formation (43,48). In addition, MMP9 tissue and serum levels correlate with disease activity in UC (1,28,35).…”

mentioning

confidence: 89%

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Liu

Patel

Walter

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 304: G793-G803, 2013. First published March 7, 2013 doi:10.1152/ajpgi.00249.2012.-Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)-and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSSand S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc. inflammation; dextran sodium sulfate; transgenic mice; IL-8 INFLAMMATORY BOWEL DISEASE (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease that affects the entire gastrointestinal (GI) tract and the colonic mucosa and is associated with an increased risk for colon cancer. IBD is characterized by relapses (acute flare) and remissions, which are related to genetic basis and involve immune-mediated tissue injury followed by repair. Recent studies have shown that cytokines play a key role in regulating IBD (9, 40). There is increased incidence of IBD in urban areas of industrialized nations (29,42). Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes with proteolytic activity against extracellular matrix (ECM) proteins and are also known to play an important role for normal tissue remodeling (47). MMPs have also been shown to be involved in several pathological conditions such as IBD, tumor invasion, and colorect...

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“…Under physiological conditions, colonic trypsin activity is constantly counterbalanced by the presence of trypsin inhibitors [43]. On the contrary, in patients with inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, there is a reduction of the expression of the trypsin inhibitor [44] [45] and thus, trypsin activity is increased in IBD patients [46]. Indeed, this phenomenon has also been observed in animal models of colitis [47].…”

Section: Endogenous Proteases and Pain Related To Protease-activated mentioning

confidence: 99%

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Cenac

2013

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Abstract:The protease-activated receptors (PARs) play a pivotal role in inflammatory and nociceptive processes. PARs have raised considerable interest because of their capacity to regulate numerous aspects of viscera physiology and pathophysiology. The present article summarizes research on PARs and proteases as signalling molecules in visceral pain. In particular, experiments in animal models suggest that PAR 2 is important for visceral hypersensitivity. Moreover, endogenous PAR 2 agonists seem to be released by colonic tissue of patients suffering from irritable bowel syndrome, suggesting a role for this receptor in visceral pain perception. Thus, PARs, together with proteases that activate them, represent exciting targets for therapeutic intervention on visceral pain.

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The Role of Up-Regulated Serine Proteases and Matrix Metalloproteinases in the Pathogenesis of a Murine Model of Colitis

Cited by 94 publications

References 32 publications

Trypsin-Sensitive Modulation of Intestinal Epithelial MD-2 as Mechanism of Lipopolysaccharide Tolerance

Trypsin-Sensitive Modulation of Intestinal Epithelial MD-2 as Mechanism of Lipopolysaccharide Tolerance

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

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