Inflammatory cytokines down-regulate the barrier-protective prostasin-matriptase proteolytic cascade early in experimental colitis

Abstract

Compromised gastrointestinal barrier function is strongly associated with the progressive and destructive pathologies of the two main forms of irritable bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Matriptase is a membrane-anchored serine protease encoded by uppression ofumorigenicity- ( gene, which is critical for epithelial barrier development and homeostasis. Matriptase barrier-protective activity is linked with the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin, which is a co-factor for matriptase zymogen activation. Here we show that mRNA and protein expression of both matriptase and prostasin are rapidly down-regulated in the initiating inflammatory phases of dextran sulfate sodium (DSS)-induced experimental colitis in mice, and, significantly, the loss of these proteases precedes the appearance of clinical symptoms, suggesting their loss may contribute to disease susceptibility. We used heterozygous hypomorphic mice expressing a promoter-linked β-gal reporter to show that inflammatory colitis suppresses the activity of the gene promoter. Studies in colonic T84 cell monolayers revealed that barrier disruption by the colitis-associated Th2-type cytokines, IL-4 and IL-13, down-regulates matriptase as well as prostasin through phosphorylation of the transcriptional regulator STAT6 and that inhibition of STAT6 with suberoylanilide hydroxamic acid (SAHA) restores protease expression and reverses cytokine-induced barrier dysfunction. Both matriptase and prostasin are significantly down-regulated in colonic tissues from human subjects with active ulcerative colitis or Crohn's disease, implicating the loss of this barrier-protective protease pathway in the pathogenesis of irritable bowel disease.

Impaired Intestinal Sodium Transport in Inflammatory Bowel Disease: From the Passenger to the Driver's Seat

“…J o u r n a l P r e -p r o o fElectrogenic sodium absorption and IBD: lessons learned from SPINT2 mutations Serine Peptidase Inhibitor, Kunitz Type 2 (SPINT2) (OMIM 605124; DIAR3) is a transmembrane Kunitz-type serine protease inhibitor that is widely expressed in epithelial compartments[56].SPINT2 is known to be involved in the regulation of the activities of several serine proteases, including matriptase (ST14) and prostasin (PRSS8). These enzymes are important in cell surface proteolytic pathways that are required for epithelial function and protection against chronic inflammation that would predispose to IBD[56,57]. Mutations in the SPINT2 gene cause a syndromic form of congenital sodium diarrhoea (SCSD) (Diarrhoea 3; OMIM 270420), a rare autosomal recessive disorder that occurs during early life, associated with intractable watery diarrhoea, dehydration, multiple anatomical anomalies, failure to thrive, and dependence on parenteral nutrition.…”

Mucosal lesions of the upper gastrointestinal tract in patients with ulcerative colitis: A review

“…T helper (Th) cells are key elements to the adaptive immune response. UC is mainly activated by Th2 cells-induced immune response[ 108 ]. Th2 cells are mainly induced by IL-13 and then subsequently secrete IL-4, IL-5, and IL-13, in which IL-13 is considered essential to the pathogenesis of UC[ 109 ].…”

Signal transducer and activator of transcription 6 as a target in colon cancer therapy (Review)

“…The downregulation of matriptase and prostasin, two membrane-anchored serine proteases important for the epithelial barrier development and for homeostasis, was observed in a dextran sulfate sodium (DSS)-induced model of colitis in mice and in colonic tissues from human subjects with active UC and CD (31). When STAT6 was inhibited by suberoylanilide hydroxamic acid (SAHA), the expression levels of matriptase and prostasin were restored and barrier dysfunction was decreased, implicating STAT6 signaling in the loss of the barrier-protective protease pathway (31). Enterochromaffin cells, which are responsible for synthesizing serotonin to increase epithelial cell secretion, express IL-13R (32).…”