Although studies have indicated that both Kupffer cell cyclic adenosine monophosphate (cAMP) and circulating TNF levels increase following trauma-hemorrhage and resuscitation, it remains unknown whether the elevated TNF levels are responsible for the increased Kupffer cell cAMP levels. To determine this, recombinant murine TNF-α (1.2 × 107 U/mg) was infused intravenously (.25 mg/kg body wt) over 30 min in normal rats. At 1 h after TNF-α or vehicle infusion, Kupffer cells and hepatocytes were isolated and cAMP levels were determined by radioimmunoassay. The levels of cAMP in the spleen and kidney were also measured. In addition, the maximal binding capacity and affinity of β-adrenergic receptors were determined in Kupffer cells and hepatocytes by using [125l]iodopindolol. To determine whether there is any correlation between Kupffer cell cAMP and prostaglandin E2 (PGE2) or epinephrine, plasma levels of catecholamines and PGE2 were measured. The results indicated that TNF-α infusion significantly increased Kupffer cell cAMP levels while hepatocyte cAMP levels were not altered. Moreover, cAMP levels also increased in the macrophage/lymphocyte-rich spleen but were not altered in the kidney. Kupffer cell ß-receptor binding characteristics were not significantly affected by TNF-a infusion. In contrast, TNF-α administration markedly increased plasma levels of PGE2 and epinephrine. Thus, the elevated Kupffer cell cAMP levels induced by TNF-α are not due to upregulation of β-adrenergic receptors, but may be associated with the elevated levels of circulating PGE2 and/or epinephrine. © 1995 The Shock Society.