Role of mast cells and protease-activated receptor-2 in cyclooxygenase-2 expression in urothelial cells.
Mast cells have been shown to play a role in development and persistence of various inflammatory bladder disorders. Mast cell-derived tryptase specifically activates protease-activated receptor-2 (PAR-2), and PAR-2 is known to be involved in inflammation. We investigated whether mast cells participate in increase of cyclooxygenase-2 (COX-2) protein abundance in urothelium/suburothelium of bladders of mice subsequent to cyclophosphamide (CYP)-induced bladder inflammation. We also used primary cultures of human urothelial cells to investigate cellular mechanisms underlying activation of PAR-2 resulting in increased COX-2 expression. We found that treatment of mice with CYP (150 mg/kg ip) increased COX-2 protein abundance in bladder urothelium/suburothelium 3, 6, and 24 h after CYP (P < 0.01), and increased COX-2 protein abundance was prevented by treatment of mice with the mast cell stabilizer sodium cromolyn (10 mg/kg ip) for 4 consecutive days before CYP treatment. Incubation of freshly isolated mouse urothelium/suburothelium with a selective PAR-2 agonist, 2-furoyl-LIGRLO-amide (3 microM), also increased COX-2 protein abundance (P < 0.05). We further demonstrated that 2-furoyl-LIGRLO-amide (3 microM) increased COX-2 mRNA expression and protein abundance in primary cultures of human urothelial cells (P < 0.01), and the effects of PAR-2 activation were mediated primarily by the ERK1/2 MAP kinase pathway. These data indicate that there are functional interactions among mast cells, PAR-2 activation, and increased expression of COX-2 in bladder inflammation.
Wang
Zun-Yi
ZY
Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53719, USA. wangz@svm.vetmed.wisc.edu
Wang
Peiqing
P
Bjorling
Dale E
DE
D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D004205:Cromolyn Sodium / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D001743:Urinary Bladder / Q000201:enzymology* / Q000276:immunology; D019459:Urothelium / Q000201:enzymology / Q000276:immunology
C487404:2-furoyl-LIGRLO-amide; D009842:Oligopeptides; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D003520:Cyclophosphamide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004205:Cromolyn Sodium
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