Protease-activated receptor-2 activation: a major actor in intestinal inflammation

Abstract

The role of endogenous PAR(2) in the gut is pro-inflammatory and independent of the T helper-1 or -2 cytokine profile. Endogenous PAR(2) activation controls leukocyte recruitment in the colon and thus appears as a new potential therapeutic target for the treatment of inflammatory bowel disease.

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

“…DSS-induced colitis is a useful model to study the early initiating event in IBD, such as the neutrophil recruitment to the intestinal wall and the enhanced production of proinflammatory cytokines that typifies the inflammatory cascade (33,34). Among the properties of n-3 PUFA-derived mediators (10, 13), PD1 n-3 DPA or RvD5 n-3 DPA displayed potent bio-actions that are relevant to the pathophysiology of IBD, including their ability to regulate neutrophil recruitment (vide infra).…”

Insulin Modulates Protease-Activated Receptor 2 Signaling: Implications for the Innate Immune Response

“…In contrast, our data now reveal that reciprocally insulin action can diminish a number of inflammatory parameters triggered by an acute stimulation of the innate immune system itself, as typified by PAR 2 activation. Because the PAR 2 system appears to play a prominent role in inflammatory diseases, such as arthritis (27) and intestinal inflammatory disease (3,4,11,28), one can suggest that PAR 2 activation also may enhance inflammatory responses in type 1 and type 2 diabetes. It is thus of much interest that insulin itself can be a negative regulator of the acute inflammatory action of PAR 2 .…”

“…Because the inflammatory action of PAR 2 in the paw edema model is known to involve the endothelium-dependent recruitment of inflammatory leukocytes (7,11), we evaluated the effects of insulin on PAR 2 -induced leukocyte rolling and adhesion onto the endothelial wall in vivo. Leukocyte trafficking in the microcirculation of intestinal venules was monitored both before and at different times after the intraluminal administration of PAR 2-AP alone or in combination with insulin.…”

“…These inflammatory actions of trypsin, due in large part to a neurogenic mechanism (9), are mimicked by the receptor-selective PAR 2 -activating peptide (PAR 2 -AP) SLIGRL-NH 2 . A number of studies have highlighted, particularly for PAR 2 , a prominent inflammatory role as a mediator of innate immunity, singling out PAR 2 as a new molecular target for anti-inflammatory and analgesic treatments (10,11). Although some studies have identified factors that are able to control the expression of PAR 2 , no studies have identified so far the endogenous signaling pathways that can modulate its proinflammatory effects.…”

Tissue Factor-Dependent Chemokine Production Aggravates Experimental Colitis

“…In line with this notion, activation of PAR-2 by either the TF/FVIIa complex or agonist peptides leads to IL-8 production in several cell lines, including epithelial cells of the gastrointestinal tract (47,50,51), but also in the whole colon section (this report). Moreover, promoter methylation of PAR-2 seems to correlate with the severity of ulcerative colitis (52), and PAR-2 deficiency was protective in DSS-, 2,4,6-trinitrobenzenesulfonic acid (TNBS)-and oxazolone-induced colitis (53). Most importantly, endogenous PAR-2 seemed to aggravate experimental colitis by inducing leukocyte recruitment toward the colon.…”