Impairment of cell-mediated immunity is both a common manifestation of critical illness and a potential cause of increased infectious morbidity and mortality. The mechanisms responsible for alterations in systemic immune regulation are incompletely understood; however, monocytes and fixed tissue macrophages appear to play a central role. We have previously shown that infusion of gram-negative organisms into the portal vein, but not into the systemic circulation, induces suppression of delayed hypersensitivity responsiveness in vivo and of mitogen-stimulated lymphocyte proliferation in vitro. The present studies were undertaken to probe the mechanisms of this suppression. Rats received 3 x 10(8) killed Pseudomonas aeruginosa via the inferior vena cava or the portal vein; they were sacrificed 24 hr later and the mitogen-driven proliferative responses of isolated splenocytes were assayed. Portal infusion resulted in significant suppression of Con A-induced proliferative responses (15.5 +/- 2.7 cpm x 10(-3) compared to 68.6 +/- 9.8 cpm x 10(-3) for infrahepatic vena cava-infused animals and 48.0 +/- 5.4 cpm x 10(-3) for nonoperated controls). Suppression was shown to be a consequence of the release of a soluble suppressive factor from splenic adherent cells. Suppression of the proliferative responses of control lymphocytes could also be induced by a soluble factor present in culture supernatants of alveolar macrophages harvested from portally infused animals (4.7 +/- 0.4 cpm x 10(-3) vs 88.6 +/- 27 cpm x 10(-3) for systemically infused animals and 60.1 +/- 8.4 cpm x 10(-3) for nonoperated controls). The stimulus for the release of this factor was not endotoxin, but a second factor released from the liver.(ABSTRACT TRUNCATED AT 250 WORDS)