TUMOR-NECROSIS-FACTOR-ALPHA ADMINISTRATION INCREASES KUPFFER CELL CYCLIC ADENOSINE-MONOPHOSPHATE LEVELS

Although studies have indicated that both Kupffer cell cyclic adenosin e monophosphate (cAMP) and circulating TNF levels increase following t rauma-hemorrhage and resuscitation, it remains unknown whether the ele vated TNF levels are responsible for the increased Kupffer cell cAMP l evels. To determine this, recombinant murine TNF-alpha (1.2 x 10(7) U/ mg) was infused intravenously (.25 mg/kg body wt) over 30 min in norma l rats. At 1 h after TNF-alpha or vehicle infusion, Kupffer cells and hepatocytes were isolated and cAMP levels were determined by radioimmu noassay. The levels of cAMP in the spleen and kidney were also measure d. In addition, the maximal binding capacity and affinity of beta-adre nergic receptors were determined in Kupffer cells and hepatocytes by u sing [I-125]iodopindolol. To determine whether there is any correlatio n between Kupffer cell cAMP and prostaglandin E(2) (PGE(2)) or epineph rine, plasma levels of catecholamines and PGE(2) were measured. The re sults indicated that TNF-alpha infusion significantly increased Kupffe r cell cAMP levels while hepatocyte cAMP levels were not altered. More over, cAMP levels also increased in the macrophage/lymphocyte-rich spl een but were not altered in the kidney. Kupffer cell beta-receptor bin ding characteristics were not significantly affected by TNF-alpha infu sion. In contrast, TNF-alpha administration markedly increased plasma levels of PGE(2) and epinephrine. Thus, the elevated Kupffer cell cAMP levels induced by TNF-alpha are not due to upregulation of beta-adren ergic receptors, but may be associated with the elevated levels of cir culating PGE(2) and/or epinephrine.