The International Journal of Biochemistry & Cell Biology
ReviewProteinase-activated receptors (PARs) in infection and inflammation in the gut
Section snippets
PARs in the gut: expression and functions
Four members of this family of seven transmembrane domain G protein-coupled receptors have been cloned: PAR1 to PAR4. Some of the members of this family can be activated by the same proteinases: for example, PAR1, PAR3 and PAR4 are activated by thrombin, PAR2 and PAR4 are activated by trypsin, but others can show some specificity: for example, tryptase activates only PAR2 (Vergnolle, 2005) (see Table 1). PARs are expressed in intestinal epithelial cells (PAR1, PAR2, PAR4) (Mule, Pizzuti,
PARs in intestinal epithelium functions
In intestinal epithelial cells, PARs are expressed both on the apical and the basolateral surfaces, which suggests that it can be activated by different types of proteinases: luminal, circulating, secreted, of even membrane-associated proteinases. Both the apical and basolateral surfaces are potentially exposed to high concentrations of proteinases originating from the host, or from the gut flora.
Apical stimulation of intestinal epithelial monolayers by selective PAR1 agonists increases
PARs and intestinal immune cells
Evidences for functionality of PARs (PAR1, PAR2 and PAR3) in T-cells have been raised and studies on post-ligand signaling cascades have identified tyrosine phosphorylation of Vav1 as a common event to PAR activation in lymphocytes (Bar-Shavit et al., 2002). Other studies have shown that monocytic cells isolated from the lamina propria of mice can be stimulated by PAR1 or PAR2 selective agonists modifying the release of inflammatory cytokines (Fiorucci et al., 2001; Vergnolle et al., 2004). In
PARs and neuro-immune functions
Since the discovery that proteinases can signal to neurons through the activation of PARs (Steinhoff et al., 2000), and because of the strong expression of PAR1, PAR2 and PAR4 on enteric neurons (Gao et al., 2002; Kayssi, Amadesi, Bautista, Bunnett, & Vanner, 2007; Mule et al., 2004), the role of PARs as activators or modulators of neuro-immune functions has been more particularly studied. It has been established that PAR2 (Nguyen et al., 2003), but not PAR1 (Vergnolle et al., 2004) local
PAR-activating proteinases in the gut
Proteinases represent 2% of the human genome and are present at high concentrations, particularly in the gastrointestinal tract. Because of the potential harmful consequences of tissue exposure to high proteolytic activity, the release, activity and degradation of proteolytic enzymes must be tightly regulated. In order to be activated, PARs need to see active proteinases to be released in their vicinity and in a timely manner. Whether this release occurs in particular pathophysiological
Relevance of PARs in innate immune diseases of the gut
Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gut that affect mostly the large and small intestine. Although the etiology of the disease is still debated, the consensus hypothesis is that in genetically predisposed individuals, both environmental factors (luminal bacteria) and endogenous factors (defective immune response, defective intestinal barrier, hypo-responsive enteric nervous system) induce a mucosal immune response that is aberrant in either its
Concluding remarks
Because of the wide distribution of PARs in different cell types of the gut and the opposite effects that are sometimes observed: i.e.PAR1 activation on intestinal epithelial cells provokes apical chloride secretion, while PAR1 activation on enteric neurons suppresses luminal chloride secretion, it has been difficult to clearly define the role of each PARs in gut diseases. Depending on the tissues or cell types in which PARs are activated, and depending on the type of stimuli (chronic
Acknowledgments
NV is supported by an INSERM-Avenir grant, by the “Fondation Bettencourt-Schueller”, and by the “Institut UPSA de la Douleur”.
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