title: Inhibition of vasoactive intestinal polypeptide (VIP) induces resistance to dextran sodium sulfate (DSS)-induced colitis in mice.
abstract: VIP is highly expressed in the colon and regulates motility, vasodilatation, and sphincter relaxation. However, its role in the development and progress of colitis is still controversial. Our aim was to determine the participation of VIP on dextran sodium sulfate (DSS)-induced colonic mucosal inflammation using VIP(-/-) and WT mice treated with VIP antagonists. Colitis was induced in 32 adult VIP(-/-) and 14 age-matched WT litter-mates by giving 2.5 % DSS in the drinking water. DSS-treated WT mice were injected daily with VIP antagonists, VIPHyb (n = 22), PG 97-269 (n = 9), or vehicle (n = 31). After euthanasia, colons were examined; colonic cytokines mRNA were quantified. VIP(-/-) mice were remarkably resistant to DSS-induced colitis compared to WT. Similarly, DSS-treated WT mice injected with VIPHyb (1 μM) or PG 97-269 (1 nM) had significantly reduced clinical signs of colitis. Furthermore, colonic expression of IL-1ϐ, TNF-α, and IL-6 was significantly lower in VIP(-/-) and VIPHyb or PG 97-269 compared to vehicle-treated WT. Genetic deletion of VIP or pharmacological inhibition of VIP receptors resulted in resistance to colitis. These data demonstrate a pro-inflammatory role for VIP in murine colitis and suggest that VIP antagonists may be an effective clinical treatment for human inflammatory bowel diseases.
authors.affiliation: CURE/Digestive Diseases Research Center, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles and VA Greater Los Angeles Health Care System, Los Angeles, CA, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Vu
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Million
authors.forename: Muriel
authors.initials: M
authors.lastname: Larauche
authors.forename: Leon
authors.initials: L
authors.lastname: Luong
authors.forename: Joshua
authors.initials: J
authors.lastname: Norris
authors.forename: James A
authors.initials: JA
authors.lastname: Waschek
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Pisegna
authors.forename: Patrizia M
authors.initials: PM
authors.lastname: Germano
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D017353:Gene Deletion; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009496:Neurotensin / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D007378:Interleukins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C069189:(VIP-neurotensin) hybrid antagonist; D014660:Vasoactive Intestinal Peptide; D009496:Neurotensin; D016264:Dextran Sulfate