title: Selective targeting of Kupffer cells with liposomal butyrate augments portal venous transfusion-induced immunosuppression.
abstract: BACKGROUND
  Enhanced Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E2 (PGE2) has been shown to be a mechanism of the immunosuppressive effect of portal venous transfusions (PVT). Butyrate, a four-carbon short-chain fatty acid, has received increased attention because of its ability to enhance gene transcription. This study tested the hypothesis that the intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production and thus augments the immunosuppressive effect of PVT.
  
  
  METHODS
  Butyrate was incorporated into liposomes and administered intravenously to Lewis rats. Control rats were administered liposomes without butyrate. Twenty-four hours after liposome injection, rats were administered a PVT of 1 ml of Wistar-Furth blood. Kupffer cells were isolated, and PGE2 and tumor necrosis factor-alpha levels were measured in the culture medium after 24 hr. Additionally, Kupffer cells from butyrate-treated and control animals were added to one-way mixed lymphocyte reaction cultures.
  
  
  RESULTS
  Intrahepatic delivery of butyrate via liposomes increased Kupffer cell PGE2 (3800+/-1220 vs. 1010+/-119 pg/ml, P<0.05) and decreased tumor necrosis factor-alpha (1670+/-81 vs. 3360+/-415 pg/ml, P<0.01) production as compared with controls. Butyrate also augmented the Kupffer cell-mediated immunosuppression as demonstrated by significant depression of the mixed lymphocyte reaction (690+/-119 vs. 3850+/-148 cpm, P<0.01).
  
  
  CONCLUSIONS
  The results support the hypothesis that intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production, and specific targeting of Kupffer cells with liposomes containing immunomodulating agents such as butyrate may be a useful means of augmenting immunosuppression protocols in organ transplantation.
authors.affiliation: Department of Surgery, University of California, Davis School of Medicine, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Perez
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.forename: N E
authors.initials: NE
authors.lastname: Hubbard
authors.forename: K
authors.initials: K
authors.lastname: Erickson
authors.forename: M
authors.initials: M
authors.lastname: Morgan
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: S M
authors.initials: SM
authors.lastname: Rudich
authors.forename: S
authors.initials: S
authors.lastname: Katznelson
authors.forename: J B
authors.initials: JB
authors.lastname: German
mesh_terms: D000818:Animals; D001803:Blood Transfusion; D002087:Butyrates / Q000008:administration & dosage* / Q000494:pharmacology; D020148:Butyric Acid; D015232:Dinoprostone / Q000096:biosynthesis; D004337:Drug Carriers; D007107:Immune System / Q000502:physiology; D007165:Immunosuppression Therapy / Q000379:methods*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008081:Liposomes; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D011169:Portal Vein; D051381:Rats; D011920:Rats, Inbred WF; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D002087:Butyrates; D004337:Drug Carriers; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D020148:Butyric Acid; D015232:Dinoprostone