title: Paradoxical regulation of ChAT and nNOS expression in animal models of Crohn's colitis and ulcerative colitis.
abstract: Morphological and functional changes in the enteric nervous system (ENS) have been reported in inflammatory bowel disease. We examined the effects of inflammation on the expression of choline acetyltransferase (ChAT) and nNOS in the muscularis externae of two models of colonic inflammation, trinitrobenzene sulfonic acid (TNBS)-induced colitis, which models Crohn's disease-like inflammation, and DSS-induced colitis, which models ulcerative Colitis-like inflammation. In TNBS colitis, we observed significant decline in ChAT, nNOS, and protein gene product (PGP) 9.5 protein and mRNA levels. In DSS colitis, ChAT and PGP9.5 were significantly upregulated while nNOS levels did not change. The nNOS dimer-to-monomer ratio decreased significantly in DSS- but not in TNBS-induced colitis. No differences were observed in the percentage of either ChAT (31 vs. 33%)- or nNOS (37 vs. 41%)-immunopositive neurons per ganglia or the mean number of neurons per ganglia (55 ± 5 vs. 59 ± 5, P > 0.05). Incubation of the distal colon muscularis externae in vitro with different types of inflammatory mediators showed that cytokines decreased ChAT and nNOS expression, whereas H₂O₂, a component of oxidative stress, increased their expression. NF-κB inhibitor MG-132 did not prevent the IL-1β-induced decline in either ChAT or nNOS expression. These findings showed that TNBS- and DSS-induced inflammation differentially regulates the expression of two critical proteins expressed in the colonic myenteric neurons. These differences are likely due to the exposure of the myenteric plexus neurons to different combinations of Th1-type inflammatory mediators and H₂O₂ in each model.
authors.affiliation: Division of Gastroenterology, Dept. of Internal Medicine, The Univ. of Texas Medical Branch at Galveston, 8.104 Medical Research Bldg., Galveston, TX 77555-1064. jhwinsto@utmb.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Winston
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Li
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Sarna
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000294:innervation* / Q000473:pathology; D003424:Crohn Disease / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007976:Leupeptins; D016328:NF-kappa B; D012333:RNA, Messenger; D009569:Nitric Oxide; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D006861:Hydrogen Peroxide; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D002795:Choline O-Acetyltransferase; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; D000109:Acetylcholine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: choline acetyltransferase; enteric neurons; motility; neuronal nitric oxide synthase; smooth muscle