Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum.
Corticotropin-releasing factor (CRF) and the closely related family of neuropeptides urocortins (Ucns) are ancient paracrine-signaling peptides secreted in both the central and peripheral neural circuits. CRF and Ucns released from the CNS (central) regulate a plethora of physiological processes that include food intake, inflammation, and bowel motility and permeability. In the gastrointestinal tract, CRF actions are largely proinflammatory, whereas the effects of the Ucn subtypes can be either pro- or antiinflammatory. Central (intracerebroventricular) or peripheral (i.p.) administration of CRF or Ucns inhibits gastric emptying and promotes colonic motility. To ascertain the role of peripherally expressed CRF and UcnII in gastrointestinal inflammation and motility, we generated ileum-specific phenotypic knockouts of these peptides by using RNA interference. Long dsRNA effectively silenced basal expression of CRF and UcnII in ileum. Control dsRNA or saline treatment did not affect CRF or UcnII expression. In an experimental model of toxin-induced intestinal inflammation, inhibition of CRF ablated the inflammatory response (measured by epithelial damage, mucosal edema, and neutrophil infiltration). UcnII dsRNA treatment did not alter the inflammatory response to toxin. Furthermore, ileal motility was increased after site-specific inhibition of both CRF and UcnII. Thus, we demonstrate that ileal-specific CRF promotes inflammation and both CRF and UcnII modulate bowel motility.
la Fleur
Susanne E
SE
Department of Surgery, University of California, San Francisco, CA 94143, USA.
Wick
Elizabeth C
EC
Idumalla
Prema S
PS
Grady
Eileen F
EF
Bhargava
Aditi
A
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006652:Histological Techniques; D007082:Ileum / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054832:Urocortins
D018076:DNA, Complementary; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone