A role for proteinase-activated receptor–1 in inflammatory bowel diseases

Abstract

Proteinase-activated receptor-1 (PAR 1 ), a G protein-coupled receptor activated by thrombin, is highly expressed in different cell types of the gastrointestinal tract. The activity of thrombin and of other proteinases is significantly increased in the colon of inflammatory bowel disease (IBD) patients. Since PAR 1 activation in tissues other than the gut provoked inflammation, we hypothesized that PAR 1 activation in the colon is involved in the pathogenesis of IBD. Here, we demonstrate that PAR 1 is overexpressed in the colon of IBD patients. In mice, intracolonic administration of PAR 1 agonists led to an inflammatory reaction characterized by edema and granulocyte infiltration. This PAR 1 activation-induced inflammation was dependent on B and T lymphocytes. Moreover, PAR 1 activation exacerbated and prolonged inflammation in a mouse model of IBD induced by the intracolonic administration of trinitrobenzene sulfonic acid (TNBS), while PAR 1 antagonism significantly decreased the mortality and severity of colonic inflammation induced by TNBS and dextran sodium sulfate. In these 2 models, colitis development was strongly attenuated by PAR 1 deficiency. Taken together, these results imply an important role for PAR 1 in the pathogenesis of experimental colitis, supporting the notion that PAR 1 inhibition may be beneficial in the context of IBD and possibly in other chronic intestinal inflammatory disorders.

Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2

“…In the gastrointestinal (GI) tract, PARs can be activated by endogenous proteases secreted by the pancreas and mast cells, and potentially by the luminal enteric microbiota, resulting in permeability of the intestinal epithelium (49). Given that increased intestinal permeability is a hallmark of IBD and that PAR expression on the gut epithelium differs between IBD patients and healthy individuals (50,51), it is possible that these receptors are involved in enteric microbial protease-mediated permeability of the intestine. Although the activation of PAR1, -2, and -4 isoforms has been linked to intestinal permeability (25,52), increased intestinal permeability induced by PAR2 has been reported to occur via disruption of the tight junctions (T-Js) between epithelial cells (paracellular permeability).…”

Insulin-like Growth Factor-1 Receptor Transactivation Modulates the Inflammatory and Proliferative Responses of Neurotensin in Human Colonic Epithelial Cells

“…Recent studies have indicated that, in addition to IGF-1 and insulin, IGF-1R can also be transactivated by several GPCRs, including thrombin (30,53), endothelin-1 and bombesin (54), and angiotensin II (31). Similar to NTR1 (17,18), other GPCRs, including the receptors for thrombin (55,56) and bombesin (57), are also shown to play dual roles in intestinal inflammation. Interestingly, these GPCRs also transactivate the EGFRs that stimulate MAPK activation, leading to cell proliferation (28,58).…”

Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis

“…Dextran sodium sulfate (DSS)-induced colitis is a well established experimental model of IBD used to study cytokine-triggered inflammation and injury in the colon (16,17) as well as other mechanisms of colitis such as thrombin-triggered pathways of inflammation (18). DSS colitis is characterized histologically by infiltration of inflammatory cells into the lamina propria, with lymphoid hyperplasia, focal crypt damage, and epithelial ulceration (16)(17)(18)(19).…”

“…DSS colitis is characterized histologically by infiltration of inflammatory cells into the lamina propria, with lymphoid hyperplasia, focal crypt damage, and epithelial ulceration (16)(17)(18)(19). These pathological changes are thought to develop as a result of a barrier-destructive effect of DSS on the epithelium, subsequent phagocytosis of lamina propria cells, and production of cytokines (16)(17)(18)(19). Although the relationship of murine DSSinduced colitis to the human disease remains to be established, this widely used IBD model has a number of advantages, including simplicity, high degree of uniformity of the lesions, and leukocyte infiltration (19).…”