Mitogen-activated protein kinase pathways contribute to hypercontractility and increased Ca2+ sensitization in murine experimental colitis.
Inflammatory bowel disease (IBD) is associated with intestinal smooth muscle dysfunction. Many smooth muscle contractile events are associated with alterations in Ca(2+)-sensitizing pathways. The aim of the present study was to assess the effect of colitis on Ca(2+) sensitization and the signaling pathways responsible for contractile dysfunction in murine experimental colitis. Colitis was induced in BALB/c mice by providing 5% dextran sulfate sodium (DSS) in drinking water for 7 days. Contractile responses of colonic circular smooth muscle strips to 118 mM K(+) and carbachol (CCh) were assessed. DSS induced a T(H)2 colitis [increased interleukin (IL)-4 and IL-6] with no changes in T(H)1 cytokines. Animals exposed to DSS had increased CCh-induced contraction (3.5-fold) and CCh-induced Ca(2+)-sensitization (2.2-fold) responses in intact and alpha-toxin permeabilized colonic smooth muscle, respectively. The contributions of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) to CCh-induced contractions were significantly increased during colitis. Ca(2+)-independent contraction induced by microcystin was potentiated (1.5-fold) in mice with colitis. ERK and p38MAPK (but not Rho-associated kinase) contributed to this potentiation. ERK1/2 and p38MAPK expression were increased in the muscularis propria of colonic tissue from both DSS-treated mice and patients with IBD (ulcerative colitis >> Crohn's disease). Murine T(H)2 colitis resulted in colonic smooth muscle hypercontractility with increased Ca(2+) sensitization. Both ERK and p38MAPK pathways contributed to this contractile dysfunction, and expression of these molecules was altered in patients with IBD.
Ihara
Eikichi
E
Department of Biochemistry and Molecular Biology, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada.
Beck
Paul L
PL
Chappellaz
Mona
M
Wong
Josee
J
Medlicott
Shaun A
SA
MacDonald
Justin A
JA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D003106:Colon / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D052998:Microcystins / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D016207:Cytokines; D052998:Microcystins; C078588:microcystin; D002217:Carbachol; D016264:Dextran Sulfate; D009195:Peroxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium