Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum

Susanne E. La Fleur, Elizabeth C. Wick, Prema S. Idumalla, Eileen F. Grady, Aditi Bhargava

Research output: Contribution to journalArticle

Abstract

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 Ucnll 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 Ucnll in ileum. Control dsRNA or saline treatment did not affect CRF or Ucnll 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). Ucnll dsRNA treatment did not alter the inflammatory response to toxin. Furthermore, ileal motility was increased after site-specific inhibition of both CRF and Ucnll. Thus, we demonstrate that Meal-specific CRF promotes inflammation and both CRF and Ucnll modulate bowel motility.

Original languageEnglish (US)
Pages (from-to)7647-7652
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number21
DOIs
StatePublished - May 24 2005
Externally publishedYes

Keywords

  • Corticotropin-releasing factor
  • Long dsRNA
  • RNA interference

ASJC Scopus subject areas

  • Genetics
  • General

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