Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability.
Proteinase-activated receptor 1 (PAR1)-mediated inflammation remains poorly understood. Here we characterize previously unrecognized effects of PAR1-induced apoptosis signaling, which contributes to epithelial barrier dysfunction. Incubation of epithelial cells with PAR1 agonists induced apoptosis and increased epithelial permeability in a caspase-3-dependent manner. Similarly, studies in vivo demonstrated that intracolonic infusion with PAR1 agonists increased colonic permeability in mice, and that this effect was abolished by pretreatment with a caspase-3 inhibitor. PAR1 agonists induced tight junctional zonula-occludens 1 disruption and apoptotic nuclear condensation. Investigation into signaling pathways showed that these effects were dependent on caspase-3, tyrosine kinase, and myosin light chain kinase. Conversely, the Src kinase inhibitor PP1 augmented zonula-occludens 1 injury and nuclear condensation induced by PAR1 agonists. These results support a role for proteinases and PARs in intestinal disease and provide new directions for possible therapeutic applications of PAR1 antagonists.
Chin
Alex C
AC
Department of Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 1N4.
Vergnolle
Nathalie
N
MacNaughton
Wallace K
WK
Wallace
John L
JL
Hollenberg
Morley D
MD
Buret
Andre G
AG
D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; D010750:Phosphoproteins; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D011505:Protein-Tyrosine Kinases; D009219:Myosin-Light-Chain Kinase; D020170:Caspase 1