Production of IL-1beta, hydrogen peroxide, and nitric oxide by colonic mucosa decreases sigmoid smooth muscle contractility in ulcerative colitis.
We have previously shown that sigmoid circular muscle cells from patients with ulcerative colitis (UC) exhibit reduced contraction and Ca2+ signaling in response to the neurotransmitter neurokinin A (NKA) and that IL-1beta and H2O2 may contribute to these reduced responses in UC. In addition, we have found that nitric oxide (NO) levels were significantly increased in UC circular muscle. To establish the site of origin for IL-1beta, H2O2, and NO, we assembled an in vitro system in which normal or UC mucosa were sealed between two chambers filled with oxygenated Krebs solution. Because the mucosa consists of full-thickness mucosa and submucosa, it is expected that whatever is released into the undernatant from the submucosal side may diffuse to the circular muscle layer in the intact colon. Treatment of normal sigmoid circular muscle cells for 2 h with undernatants collected from the UC submucosal side (UCS) significantly decreased contraction induced by NKA and thapsigargin and the NKA- and caffeine-induced Ca2+ signal in Ca2+-free medium. In addition, UC mucosa released into the undernatant on its submucosal side significantly more H2O2, IL-1beta, and NO than normal mucosa. The reduction in contraction and Ca2+ signal induced by UCS was partially reversed by pretreatment with an IL-1beta antibody or with catalase. The NO scavenger hemoglobin partially prevented UCS-induced reduction in contraction and Ca2+ signaling in response to NKA but not the reduced response to thapsigargin or caffeine. Sodium nitroprusside inhibited NKA but not the caffeine-induced Ca2+ signal. We conclude that in UC the mucosa releases IL-1beta, H2O2, and NO, which may contribute to the impaired Ca2+ release and altered sigmoid muscle contractility.
Cao
Weibiao
W
Dept. of Medicine, Brown Medical School and Rhode Island Hospital, 55 Claverick St., Rm. 337, Providence, RI 02903, USA. Weibiao_Cao@brown.edu
Fiocchi
Claudio
C
Pricolo
Victor E
VE
D002110:Caffeine / Q000494:pharmacology; D020013:Calcium Signaling; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000503:physiopathology*; D012809:Colon, Sigmoid / Q000378:metabolism / Q000503:physiopathology; D006454:Hemoglobins / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000503:physiopathology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015288:Neurokinin A / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D006454:Hemoglobins; D007375:Interleukin-1; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D002110:Caffeine; D019284:Thapsigargin; D015288:Neurokinin A; D006861:Hydrogen Peroxide; D002374:Catalase