Carcinoembryonic antigen induction of IL-10 and IL-6 inhibits hepatic ischemic/reperfusion injury to colorectal carcinoma cells.
Tumor cells cause ischemia/reperfusion (I/R) injury as they arrest within the hepatic microvasculature with the production of nitric oxide (NO) and reactive oxygen species (ROS) that kill both host liver and implanting tumor cells. Carcinoembryonic antigen (CEA) both facilitates the survival of experimental metastasis to nude mouse liver by weakly metastatic human colorectal carcinomas (CRCs) and induces the release of the proinflammatory cytokine IL-6. We hypothesized that CEA also stimulates the release of the antiinflammatory cytokine IL-10 causing inhibition of the toxicity of hepatic I/R injury and indirect stimulation of tumor cell colonization of the liver. Intravenous injection of CEA produced more than 1 ng/ml of IL-10 in the systemic circulation within 1 hr which subsided by 8 hr. The IL-10 response is specific to CEA since the pentapeptide sequence in CEA that binds to the CEA receptor stimulated isolated Kupffer cells to produce IL-10. IL-10, but not IL-6, increased the survival of weakly metastatic CRC cocultured with ischemic-reoxygenated liver fragments but did not affect the survival of CRC exposed to oxidative stress in the absence of any host cells. CEA, IL-6 and IL-10 pretreatment reduced expression of iNOS but only CEA and IL-10 strongly inhibited NO and total reactive species production by ischemic-rexoygenated liver. IL-6 was toxic to CRC exposed to oxidative stress while IL-10 did not have a direct effect on CRC. Thus, CEA stimulates production of IL-10 that may enhance metastasis by promoting the ability of circulating CRC cells to survive the I/R injury of implantation.
Jessup
John Milburn
JM
Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA. jmj2a5@georgetown.edu
Laguinge
Luciana
L
Lin
Shuling
S
Samara
Raed
R
Aufman
Kimberly
K
Battle
Paul
P
Frantz
Marilyn
M
Edmiston
Kirsten H
KH
Thomas
Peter
P
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000473:pathology*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology* / Q000502:physiology; D015850:Interleukin-6 / Q000494:pharmacology* / Q000502:physiology; D007700:Kinetics; D008102:Liver Circulation / Q000187:drug effects*; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D014183:Transplantation, Heterologous
D002272:Carcinoembryonic Antigen; D015850:Interleukin-6; D016753:Interleukin-10; D009569:Nitric Oxide