The mechanism by which carcinoembryonic antigen (CEA) causes enhancement of hepatic metastasis from colorectal cancer is not defined. We hypothesize that binding of CEA to an 80-kDa Kupffer cell receptor by the peptide sequence Pro-Glu-Leu-Pro-Lys (PELPK) induces cytokine production in the hepatic microenvironment, which then impacts on the formation of hepatic metastasis from colorectal cancer. We have, therefore, isolated Kupffer cells and treated them in vitro with CEA, its gene family member nonspecific cross-reacting antigen, PELPK-albumin conjugate, and lipopolysaccharide as a positive control. Spent media was examined for the content of cytokines interleukin (IL) 1alpha, IL-1beta, IL-6, and tumor necrosis factor alpha using the ELISA. Simultaneously, mRNA was extracted from the same cells and amplified using reverse transcription-PCR to evaluate the induction of specific cytokine transcripts. As expected, lipopolysaccharide stimulated cytokine production. CEA, nonspecific cross-reacting antigen, and PELPK-albumin induced secretion of all of the cytokines tested; the response was higher in general with PELPK-albumin. The levels of cytokine mRNA showed a similar profile. These responses were not seen when a similar but irrelevant peptide conjugate PELGK-albumin was used. These results demonstrate that binding of the peptide PELPK to the 80-kDa receptor results in the release of a series of cytokines that have the potential to activate hepatic sinusoidal endothelium. This may explain CEA-induced enhancement of experimental hepatic metastasis.