Activation of Kupffer cells inhibits tumor growth in a murine model system.
Kupffer cells, a liver organ-specific macrophage, play an important role in preventing the development of malignant tumors. The mechanism responsible for their tumoricidal activities is not completely known. In our study, we established in vivo models involving a rat malignant cell line, rat Kupffer cells and tumor implantation in nude mice. A series of relevant in vitro experiments were also carried out to determine possible pathways. LPS-activated Kupffer cells produced significant amounts of NO, TNFalpha and IFNgamma. Malignant cells treated with either Kupffer cells or culture supernatant of the activated Kupffer cells had an increase in caspase-8 activity. Implanted tumors originated from malignant cells treated with either Kupffer cells or culture supernatant of the activated Kupffer cells grew much smaller than those from malignant cells without treatment or treated with control supernatants. The alteration of anti-apoptotic Bcl-2 was inversely associated with the change of pro-apoptotic caspase-8 and their levels in the tumor tissues matched the size of the tumors and treatments they received. It appeared that the above changes resulted in an increase in cellular DNA damage and apoptosis seen in malignant cells. Therefore, Kupffer cells execute their anti-tumor effect via increasing the production of NO, TNFalpha and IFNgamma and these cytotoxic molecules inhibit the growth of tumor by damaging cellular DNA and inducing apoptosis that was featured by downregulation of Bcl-2 but upregulation of caspase-8.
Chen
George G
GG
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. gchen@cuhk.edu.hk
Lau
Wan Y
WY
Lai
Paul B S
PB
Chun
Ying S
YS
Chak
Ernest C W
EC
Leung
Billy C S
BC
Lam
Isa K Y
IK
Lee
Janet F Y
JF
Chui
Albert K K
AK
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004249:DNA Damage; D005910:Glioma / Q000473:pathology / Q000517:prevention & control; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000032:analysis; D007728:Kupffer Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases