CARCINOEMBRYONIC ANTIGEN INDUCES CYTOKINE EXPRESSION IN KUPFFER CELLS- IMPLICATIONS FOR HEPATIC METASTASIS FROM COLORECTAL-CANCER

The mechanism by which carcinoembryonic antigen (CEA) causes enhanceme nt of hepatic metastasis from colorectal cancer is not defined. We hyp othesize that binding of CEA to an 80-kDa Kupffer cell receptor by the peptide sequence Pro-Glu-Leu-Pro-Lys (PELPK) induces cytokine product ion in the hepatic microenvironment, which then impacts on the formati on of hepatic metastasis from colorectal cancer. We have, therefore, i solated Kupffer cells and treated them in vitro with CEA, its gene fam ily member nonspecific cross-reacting antigen, PELPK-albumin conjugate , and lipopolysaccharide as a positive control. Spent media was examin ed for the content of cytokines interleukin (IL) 1 alpha, IL-1 beta, I L-6, and tumor necrosis factor alpha using the ELISA. Simultaneously, mRNA was extracted from the same cells and amplified using reverse tra nscription-PCR to evaluate the induction of specific cytokine transcri pts. As expected, lipopolysaccharide stimulated cytokine production. C EA, nonspecific cross-reacting antigen, and PELPK-albumin induced secr etion of all of the cytokines tested; the response was higher in gener al with PELPK-albumin. The levels of cytokine mRNA showed a similar pr ofile. These responses were not seen when a similar but irrelevant pep tide conjugate PELGK-albumin was used. These results demonstrate that binding of the peptide PELPK to the 80-kDa receptor results in the rel ease of a series of cytokines that have the potential to activate hepa tic sinusoidal endothelium. This may explain CEA-induced enhancement o f experimental hepatic metastasis.