Kupffer cell-mediated lymphocyte apoptosis: a PGE2-dependent mechanism of portal venous transfusion-induced immunosuppression?
BACKGROUND
Kupffer cells, after exposure to alloantigen via the portal vein, mediate an immunosuppressive effect involving enhanced production of PGE2. We hypothesize that up-regulation of Kupffer cell CoA-independent transacylase (CoA-IT) by portal venous transfusion (PVT) is a possible mechanism of increased PGE2 production. Additionally, enhanced lymphocyte apoptosis, a process known to be macrophage dependent and facilitated by PGE2, is postulated as a possible mechanism of PVT-induced, Kupffer cell-mediated immunosuppression.


METHODS
Lewis rat Kupffer cells were isolated after portal venous infusion with 1 ml of Wistar-Firth blood (PVT) or saline (PV sal). Kupffer cell PGE2 production and CoA-IT activity was assessed. Lymphocyte apoptosis after exposure to PVT or PV sal-treated Kupffer cells was also assessed by flow cytometry.


RESULTS
PVT-treated Kupffer cells produced significantly more PGE2 and had increased CoA-IT activity when compared to PV sal-treated Kupffer cells. Treatment of Kupffer cells with a selective inhibitor of CoA-IT significantly decreased PVT-induced Kupffer cell PGE2 production. Increased lymphocyte apoptosis was observed after coculture with PVT-treated Kupffer cells compared to PV sal-treated cells.


CONCLUSIONS
PVT increases Kupffer cell PGE2 production via increased CoA-IT activity and induces Kupffer cell-mediated lymphocyte apoptosis. Lymphocyte apoptosis facilitated by Kupffer cells within the hepatic sinusoid may be an important mechanism of PVT-induced immunosuppression in organ transplantation.
Perez
R
R
Department of Surgery, University of California, Davis, Sacramento, California 95817, USA. rvperez@ucdavis.edu
Johnson
J
J
Winkler
J D
JD
Rudich
S
S
Carter
L
L
Katznelson
S
S
German
J B
JB
D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001803:Blood Transfusion; D015232:Dinoprostone / Q000378:metabolism*; D005434:Flow Cytometry; D007165:Immunosuppression Therapy; D007728:Kupffer Cells / Q000201:enzymology / Q000276:immunology*; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D011169:Portal Vein; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF
D000217:Acyltransferases; C039766:arachidonyl transacylase; D015232:Dinoprostone