In vivo induction of murine cytokine production by carcinoembryonic antigen.
Carcinoembryonic antigen (CEA) may promote experimental metastasis through production of cytokines. The effect of systemic CEA on the production of proinflammatory cytokines was investigated in mice and compared to levels induced by lipopolysaccharide (LPS). Serum concentrations of interleukin (IL)-6 peaked 1 h after an i.v. CEA injection of 40 microg/mouse to 37-54% of the maximal level induced by a 1 microg/mouse injection of LPS in both normal and immunoincompetent mice. The CEA induction of IL-6 was a specific response, because the peptide PELPK (the pentapeptide on CEA that is the ligand for the CEA receptor on Kupffer cells) conjugated to albumin induced 30% of the maximal CEA response for IL-6, whereas the specificity control PELGK-conjugated albumin did not. IL-1alpha 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 responses of mice pretreated with 100 microg/kg genistein were decreased by more than 40%. However, genistein inhibited the TNF-alpha response to LPS by 46% but increased the CEA-induced response by 300%. When murine Kupffer cells were stimulated with LPS or CEA in vitro, LPS increased tyrosine phosphorylation of a Mr 30,000 protein, whereas CEA decreased phosphorylation of a Mr 60,000 protein and did not increase phosphorylation of the Mr 30,000 protein. Thus, i.v. CEA stimulates production of IL-6 and TNF-alpha after binding to Kupffer cells through signal transduction pathways that appear to be different from those stimulated by LPS.
Edmiston
K H
KH
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Gangopadhyay
A
A
Shoji
Y
Y
Nachman
A P
AP
Thomas
P
P
Jessup
J M
JM
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D002272:Carcinoembryonic Antigen; D016207:Cytokines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D019833:Genistein; D011505:Protein-Tyrosine Kinases