New Concepts in the Pathophysiology of Inflammatory Bowel Disease

Bamias, Giorgos; Nyce, Mark R.; Rue, Sarah A. De La; Cominelli, Fabio

doi:10.7326/0003-4819-143-12-200512200-00007

Cited by 195 publications

(126 citation statements)

References 62 publications

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“…Epithelial cells can act as antigenpresenting cells and, moreover, are avid producers of chemokines and cytokines considered central to the pathogenesis of inflammatory bowel disease such as tumor necrosis factor (TNF)-a, interleukin-1 and interleukin-6. 26 Aberrant secretion of these pro-inflammatory mediators by the epithelium is an integral part of the dysregulated immune response that initiates or perpetuates intestinal inflammation. 26 The results presented here clearly suggest that colonic glandular and surface epithelial cells are also avid producers of heparanase.…”

Section: Discussionmentioning

confidence: 99%

“…26 Aberrant secretion of these pro-inflammatory mediators by the epithelium is an integral part of the dysregulated immune response that initiates or perpetuates intestinal inflammation. 26 The results presented here clearly suggest that colonic glandular and surface epithelial cells are also avid producers of heparanase. Among the few cell types that express heparanase under normal physiological conditions are placental cytothrophoblasts, skin keratinocytes and blood borne cells such as lymphocytes, neutrophils, macrophages and platelets.…”

Section: Discussionmentioning

confidence: 99%

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Heparanase upregulation by colonic epithelium in inflammatory bowel disease

et al. 2007

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Heparanase is an endo-b-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, yielding HS fragments of still appreciable size (B5-7 kDa). Heparanase activity has long been detected in a number of cell types and tissues. Importantly, heparanase activity correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the extracellular matrix barrier. Similarly, heparanase activity was implicated in neovascularization, inflammation and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. The involvement of heparanase in inflammatory processes of the gastrointestinal tract has not been examined. Here, we utilized immunohistochemical analysis to investigate heparanase expression in acute and chronic inflammatory conditions. Heparanase expression was not detected in specimens derived from normal colon tissue. In contrast, strong heparanase staining was observed in Crohn's disease and ulcerative colitis, but not in infectious colitis. Interestingly, heparanase staining was primarily observed in epithelial rather than immune cells. Importantly, un-fractionated as well as low molecular weight heparin (enoxaparin), which exhibit a strong inhibitory activity towards heparanase, have proven efficacious in ulcerative colitis and Crohn's disease patients, suggesting that heparanase is actively involved in these pathologies and thus may be considered as a target for the development of anti-inflammatory therapies. The mammalian endoglycosidase heparanase is the predominant enzyme that degrades heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPG), the dominant proteoglycan in the extracellular matrix (ECM) and cell surfaces. 1-3 HSPG consist of a protein core to which HS side chains are covalently attached. These complex macromolecules are highly abundant in the ECM and are thought to play an important structural role, contributing to ECM integrity and insolubility. 4,5 Traditionally, heparanase activity was well correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM barrier. 6-9 A proof-of-concept of this notion has recently been established by using a specific antiheparanase ribosyme and siRNA methodology, 10 clearly implicating heparanase activity as a critical requisite for metastatic spread. Similarly, heparanase was implicated in cell dissemination associated with inflammation and autoimmunity. [11][12][13] Furthermore, heparanase activity can liberate a variety of HSPG-bound biological mediators, including cytokines and chemokines such as interferon (IFN)-g, MIP-1b, RANTES and interleukins, thus contributing to the regulation of inflammation and other immune responses. 14 Heparanase expression by the gastrointestinal tract has been documented by employing immunostaining, RT-PCR and heparanase activity analy...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

et al. 2007

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“…The pathophysiology of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is not yet completely understood [1][2][3][4][5]. In recent years, it has become clear that genetic, immunological, environmental and microbial factors contribute to the aetiology of IBD [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, it has become clear that genetic, immunological, environmental and microbial factors contribute to the aetiology of IBD [1][2][3][4][5]. The epithelial cells, the first line of defence against potentially harmful luminal antigens, are remarkably similar to hepatocytes in their ability to carry out detoxification and bio-transformation of luminal agents of dietary, bacterial or fermentative origin.…”

Section: Introductionmentioning

confidence: 99%

Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

Mencarelli¹,

Migliorati²,

Barbanti³

et al. 2010

Biochemical Pharmacology

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“…In general, IBD progresses steadily or with transient remissions throughout life [1,2]. Importantly, the recurrent disease shows similar clinical features to the previous disease episode, and it is extremely uncommon that a patient with Crohn's disease relapses with another form of disease, such as ulcerative colitis [3][4][5][6]. Thus, it is conceivable that the sequential disease episodes are driven by a group of disease-specific colitogenic CD4 + memory T cells, which may be designated as 'memory stem cells' [7] of the disease.…”

Section: Introductionmentioning

confidence: 99%

Immunosenescent colitogenic CD4⁺ T cells convert to regulatory cells and suppress colitis

et al. 2008

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Inflammatory bowel diseases progress steadily by the expansion of colitogenic CD4 + cells. However, it remains unknown whether colitogenic CD4 + cells are long-living like memory cells or exhausted like effector cells. To assess the longevity of colitogenic lamina propria (LP) CD4 + cells, we performed sequential transfers of LP CD4 + cells from colitic CD4 + CD45RB high cell-transferred SCID mice into new SCID mice. Although SCID mice transferred with colitic LP CD4 + cells stably developed colitis until at least the sixth transfer, the interval to the development of colitis gradually lengthened as the number of transfers increased. The incidence of colitis gradually decreased after the seventh transfer. Furthermore, non-colitic LP CD4 + cells from mice transferred over seven times expressed significantly higher levels of PD-1 and produced significantly lower amounts of IFN-c, TNF-a, and IL-17 than colitic LP CD4 + cells recovered after the first transfer. Most notably, we found that re-transfer of non-colitic LP CD4 + cells recovered after multiple transfers prevented the development of colitis in SCID mice co-transferred with CD4 + CD45RB high cells. Thus, colitogenic LP CD4 + cells may be exhausted over time, become non-functional, convert to regulatory cells, and finally suppress colitis in the process of immunosenescence.

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New Concepts in the Pathophysiology of Inflammatory Bowel Disease

Cited by 195 publications

References 62 publications

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

Immunosenescent colitogenic CD4⁺ T cells convert to regulatory cells and suppress colitis

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New Concepts in the Pathophysiology of Inflammatory Bowel Disease

Cited by 195 publications

References 62 publications

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

Immunosenescent colitogenic CD4+ T cells convert to regulatory cells and suppress colitis

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Product

Resources

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Immunosenescent colitogenic CD4⁺ T cells convert to regulatory cells and suppress colitis