IN-VIVO INDUCTION OF MURINE CYTOKINE PRODUCTION BY CARCINOEMBRYONIC ANTIGEN

Carcinoembryonic antigen (CEA) may promote experimental metastasis thr ough production of cytokines. The effect of systemic CEA on the produc tion of proinflammatory cytokines was investigated in mice and compare d to levels induced by lipopolysaccharide (LPS), Serum concentrations of interleukin (IL)-6 peaked 1 h after an i.v. CEA injection of 40 mu g/mouse to 37-54% of the maximal level induced by a 1 mu g/mouse injec tion of LPS in both normal anti immunoincompetent mice, The CEA induct ion of IL-6 was a specific response, because the peptide PELPK (the pe ntapeptide on CEA that is the ligand for the CEA receptor on Kupffer c ells) conjugated to albumin induced 30% of the maximal CEA response fo r IL-6, whereas the specificity control PELGK-conjugated albumin did n ot, IL-1 alpha and tumor necrosis factor (TNF)-alpha levels after i.v. injection of CEA were only 3-5% of those induced by LPS, The IL-6 res ponses of mice pretreated with 100 mu g/kg genistein were decreased bg more than 40, However, genistein inhibited the TNF-alpha response to LPS bg 46% but increased the CEA-induced response by 300%, When murine Kupffer cells were stimulated with LPS of CEA in vitro, LPS increased tyrosine phosphorylation of a M-r 30,000 protein, whereas CEA decreas ed phosphorylation of a M-r 60,000 protein and did not increase phosph orylation of the M-r 30,000 protein, Thus, i.v. CEA stimulates product ion of IL-6 and TNF-alpha after binding to Kupffer cells through signa l transduction pathways that appear to be different from those stimula ted by LPS.