title: VIP attenuation of the severity of experimental pancreatitis is due to VPAC1 receptor-mediated inhibition of cytokine production.
abstract: OBJECTIVE
  VIP receptor has been clarified to exist on immune cells, indicating its possible involvement in immunity and inflammatory response. Therefore, we investigated the effects of VIP and selective agonists for 2 subtypes of VIP receptor (VPAC1-R and VPAC2-R agonist) on acute pancreatitis.
  
  
  METHODS
  Acute pancreatitis was induced in mice by 4 intraperitoneal injections of cerulein and an injection of LPS. VIP, VPAC1-R agonist, VPAC2-R agonist, or secretin (5 nmol/body) was administered 30 minutes before and after the administration of LPS. Serum amylase and cytokine levels were determined, and histologic changes were evaluated. In vitro, IL-6 and TNF-alpha production by monocytes from the spleen was determined under the stimulation of LPS with VIP, VPAC1-R agonist, or VPAC2-R agonist, and the expression of VPAC1-R and VPAC2-R mRNA in monocytes was examined.
  
  
  RESULTS
  VPAC1-R agonist significantly decreased serum amylase, IL-6, and TNF-alpha, whereas VPAC2-R agonist markedly increased serum amylase. Histologically, VIP and VPAC1-R agonist attenuated the severity of pancreatitis, although VPAC2-R agonist or secretin showed no significant effect. In vitro, VPAC1-R and VPAC2-R mRNA were obviously expressed in monocytes. Under the stimulation with LPS, VIP presented a biphasic pattern that once decreased IL-6 production from monocytes and then enhanced at high concentration. VPAC1-R agonist reduced IL-6 levels, whereas VPAC2-R agonist increased IL-6 dose-dependently. VPAC1-R agonist reduced TNF-alpha levels in a dose-dependent manner.
  
  
  CONCLUSIONS
  VIP attenuated the experimental acute pancreatitis enzymatically and morphologically by inhibiting proinflammatory cytokine production from monocytes mainly through the VPAC1-R.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Kojima
authors.forename: Tetsuhide
authors.initials: T
authors.lastname: Ito
authors.forename: Takamasa
authors.initials: T
authors.lastname: Oono
authors.forename: Terumasa
authors.initials: T
authors.lastname: Hisano
authors.forename: Hisato
authors.initials: H
authors.lastname: Igarashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Arita
authors.forename: Ken
authors.initials: K
authors.lastname: Kawabe
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jensen
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D002108:Ceruletide; D016207:Cytokines / Q000097:blood*; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000378:metabolism; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014660:Vasoactive Intestinal Peptide; D002108:Ceruletide; D000681:Amylases