Sodium butyrate upregulates Kupffer cell PGE2 production and modulates immune function

The immunosuppressive effect of portal venous blood transfusions in organ transplantation has been well established and may be mediated by increased Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E-2 (PGE(2)). In this study, butyrate, a short-chain fatty acid known to enhance gene transcription, is hypothesized to enhance Kupffer cell PGE(2) production by altering cyclooxygenase or phospholipase A(2) (PLA(2)) activity, thus augmenting the immunosuppressive effect of portal venous transfusion. Lewis rats were given a portal venous transfusion of Wistar-Firth blood or saline 1 h prior to Kupffer cell harvest. The in vitro effects of butyrate on Kupffer cell PGE, production, cyclooxygenase, and PLA(2) activity were assessed. Kupffer cell tumor necrosis factor-alpha (TNF alpha) production was also assessed due to its sensitivity to PGE(2) and its proinflamatory effects. Kupffer cells ii om port-ally transfused animals produced significantly more PGE(2) than saline-transfused controls. Addition of butyrate to the culture medium further increased PGE(2) production by as much as sevenfold in Kupffer cells of portally transfused animals. Other short-chain fatty acids, propionate and hexanoate, did not increase PGE(2) production, Butyrate added to Kupffer cells from transfused animals slightly upregulated inducible cyclooxygenase (COX-2) mRNA levels as measured by both Northern blot and reverse-transcriptase polymerase chain reaction and increased PLA(2) activity fivefold as measured by Western blot. Kupffer cell immuue function was also affected by in vitro butyrate treatment with a significant decrease in the production of TNF alpha. Thus, butyrate may be a useful immunoregulatory agent in organ transplantation protocols which seek to enhance transcription of immunosuppressive molecules. (C) 1998 Academic Press.