LPS induces NK1.1+ alpha beta T cells with potent cytotoxicity in the liver of mice via production of IL-12 from Kupffer cells.
We recently reported that systemic administration of IL-12 into mice activates NK1.1+ alpha beta T cells with intermediate TCR (NK1+TCRint) and induces strong MHC-unrestricted cytotoxicity in C57BL/6 mice. In the present report, we examined the effect of LPS on Kupffer cells and NK1+TCRint, cells in C57BL/6 mice. Administration of LPS, as well as synthetic lipid A analogue (ONO-4007), but not detoxified LPS, induces the increase of NK1 expression of NK1+TCRint cells (NKlhighTCRint) and the acquisition of strong MHC-unrestricted cytotoxicity of these cells against NK-sensitive and NK-resistant targets as does IL-12 administration. LPS as well as ONO-4007 induced IL-12 mRNA in hepatic mononuclear cells, mainly in plastic-adherent Kupffer cells. LPS-induced cytotoxicity of hepatic mononuclear cells was greatly reduced by in vivo injections of anti-IL-12 Ab, to a lesser extent by anti-IFN-gamma Ab, but not by anti-IL-1 nor anti-TNF-alpha Ab. Pretreatment of mice with LPS induced inhibition of hepatic metastases of i.v. injected EL4 cells in C57BL/6 euthymic and athymic mice and this antimetastasis was inhibited by injection of anti-IL-12 Ab. This antimetastatic effect of LPS in the liver was also observed in different strains of mice and tumors, In contrast to IL-12, however, LPS was not so effective when administered after tumor inoculation. These results revealed that LPS (lipid A) stimulates NK1+TCRint cells through IL-12 production from Kupffer cells and suggest that bacterial components, probably including those from intestine, are activators of Kupffer cells and NK1+TCRint, cells in the liver. It is also suggested that the host condition as well as LPS-induced cytokines other than IL-12 may affect antitumor effect induced by LPS in the liver.
Takahashi
M
M
Department of Oral Surgery, Tohku University School of Dentistry, Sendai, Japan.
Ogasawara
K
K
Takeda
K
K
Hashimoto
W
W
Sakihara
H
H
Kumagai
K
K
Anzai
R
R
Satoh
M
M
Seki
S
S
D000818:Animals; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D017931:DNA Primers / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000145:classification / Q000187:drug effects* / Q000276:immunology*; D007728:Kupffer Cells / Q000276:immunology*; D008050:Lipid A / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology* / Q000276:immunology*; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*
D017931:DNA Primers; D008050:Lipid A; D008070:Lipopolysaccharides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018664:Interleukin-12