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‡, and
- Aditi Bhargava*,‡,§
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Edited by Susan E. Leeman, Boston University School of Medicine, Boston, MA, and approved March 22, 2005 (received for review November 17, 2004)
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 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.
Footnotes
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↵ § To whom correspondence should be addressed at: Department of Surgery, Center for Neurobiology of Digestive Diseases, 521 Parnassus Avenue, Room C-317, Box 0660, University of California, San Francisco, CA 94143-0660. E-mail: bhargavaa{at}surgery.ucsf.edu.
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↵ † S.E.l.F. and E.C.W. contributed equally to this work.
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Author contributions: S.E.l.F., E.C.W., and A.B. designed research; S.E.l.F., E.C.W., P.S.I., E.F.G., and A.B. performed research; A.B. contributed new reagents/analytic tools; S.E.l.F., E.C.W., P.S.I., E.F.G., and A.B. analyzed data; and S.E.l.F., E.C.W., and A.B. wrote the paper.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: CRF, corticotropin-releasing factor; Ucn, urocortin; RNAi, RNA interference; GI, gastrointestinal; TxA, toxin A; siRNA, small interfering RNA; IHC, immunohistochemistry.
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See Commentary on page 7409.
- Copyright © 2005, The National Academy of Sciences
