Proteases acting at the surface of cells generate and destroy receptor agonists and activate and inactivate receptors, thereby making a vitally important contribution to signal transduction. Certain serine proteases that derive from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast cell and neutrophil proteases), and from multiple other sources (e.g., epithelial cells, neurons, bacteria, fungi) can cleave protease-activated receptors (PARs), a family of four G protein-coupled receptors. Cleavage within the extracellular amino terminus exposes a tethered ligand domain, which binds to and activates the receptors to initiate multiple signaling cascades. Despite this irreversible mechanism of activation, signaling by PARs is efficiently terminated by receptor desensitization (receptor phosphorylation and uncoupling from G proteins) and downregulation (receptor degradation by cell-surface and lysosomal proteases). Protease signaling in tissues depends on the generation and release of proteases, availability of cofactors, presence of protease inhibitors, and activation and inactivation of PARs. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including hemostasis, repair, cell survival, inflammation, and pain. Drugs that mimic or interfere with these processes are attractive therapies: selective agonists of PARs may facilitate healing, repair, and protection, whereas protease inhibitors and PAR antagonists can impede exacerbated inflammation and pain. Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.

Protease-Activated Receptors: Contribution to Physiology and Disease

Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients. We hypothesized that luminal proteinases activate PAR-2 and induce colonic inflammation. Mice received intracolonically PAR-2 agonists (trypsin, tryptase, and a selective PAR-2-activating peptide) or control drugs (boiled enzymes, inactive peptide) and inflammatory parameters were followed at various times after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2 expression and induced an inflammatory reaction characterized by granulocyte infiltration, increased wall thickness, tissue damage, and elevated T-helper cell type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was resolved 48 hours after the intracolonic administration. PAR-2 activation also increased paracellular permeability of the colon and induced bacterial trans-location into peritoneal organs. These proinflammatory and pathophysiological changes observed in wild-type mice were not detected in PAR-2-deficient mice. Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are found at high levels in the colon lumen of patients with Crohn's disease or ulcerative colitis, our data may bear directly on the pathophysiology of human inflammatory bowel diseases.

Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2.

Angiogenesis is tightly regulated by pro- and anti-angiogenic factors. Secreting mast cells are able to induce and enhance angiogenesis via multiple in part interacting pathways. They include mast cell-derived (i) potent pro-angiogenic factors such as VEGF, bFGF, TGF-beta, TNF-alpha and IL-8, (ii) proteinases and heparin, that release heparin-binding pro-angiogenic factors lodged on cell surfaces and in the extracellular matrix (ECM), (iii) histamine, VEGF, and certain lipid-derived mediators that induce microvascular hyperpermeability having pro-angiogenic effects, (iv) chemotactic recruitment of monocytes/macrophages and lymphocytes that are able to contribute with angiogenesis-modulating molecules, (v) activation of platelets that release pro-angiogenic factors, (vi) activation of neighboring stationary non-mast cells, which secrete pro-angiogenic factors, ECM-degrading proteinases and stem cell factor which attracts, mitogenically stimulates and activates mast cells, (vii) auto- and paracrine stimulation of mast cells by stem cell factor, (viii) recruitment of mast cells by pro-angiogenic factors such as VEGF, bFGF and TGF-beta. As a result of ECM-degradation and changes in the microenvironment following initial mast cell secretion, the mast cell populations may change significantly in number, phenotype and function. In tumor models, mast cells have been shown to play a decisive role in inducing the angiogenic switch which precedes malignant transformation. There is, moreover, strong evidence that mast cells significantly influence angiogenesis and thus growth and progression in human cancers.

Mast cells and angiogenesis.

Advances in mast cell biology: new understanding of heterogeneity and function

IBD immunopathogenesis: A comprehensive review of inflammatory molecules.

Background: Histologic detection of mast cells cannot adequately reflect their function and state of activation, since degranulated mast cells may escape from histologic assessment. To better define the role of mast cells in inflammatory bowel disease, the spontaneous secretion of mast cell tryptase, a highly mast cell specific protease, was measured from colorectal samples. Methods: After detection of the initial basal tryptase release, gut mucosal samples were incubated in a modified Hanks/RPMI medium using a mucosa oxygenation system. Spontaneous tryptase secretion from 153 viable samples of 22 controls, 30 patients with Crohn disease (CD) and 19 with ulcerative colitis (UC) was followed over 4 h. Tryptase was measured by radioimmunoassay. Results: The rates of the initial basal tryptase release revealed that mast cell activation occurs during active inflammation in CD and UC. While the time course of tryptase release was similar in all three groups, spontaneous tryptase secretion (over 4 h) was found ...

Release of mast cell tryptase from human colorectal mucosa in inflammatory bowel disease.

Urinary excretion of N-methylhistamine as a marker of disease activity in inflammatory bowel disease

Immunoglobulin E and eosinophilic cationic protein in segmental lavage fluid of the small and large bowel identify patients with food allergy

Collagenous and lymphocytic colitis1,2 are rare3 diseases of unknown aetiology but several issues,1–3,5 in particular the good response to budesonide,7 are suggestive of immunopathology. Patients have watery diarrhoea without abnormal findings on colonoscopy1–5 but with increased numbers of intraepithelial lymphocytes, mast cells, and eosinophils5 on histological examination.

We report six patients seen between 1993 and 1999 who were first diagnosed as having collagenous/lymphocytic colitis. Signs of allergy entailed a work up for food allergy. (table 1)

View this table:

 Table 1 
 Patient characteristics



All patients were investigated with skin prick testing, total and allergen specific …

https://gut.bmj.com/content/gutjnl/54/2/312.full.pdf

Microscopic (collagenous and lymphocytic) colitis triggered by food allergy.

Methylhistamine in Crohn's disease (CD): Increased production and elevated urine excretion correlates with disease activity

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