Tolerance to the anti-metastatic effect of lipopolysaccharide against liver metastasis in mice.
We describe the involvement of endotoxin tolerance in the refractoriness of its anti-metastatic effect against murine syngeneic tumors. Three i.v. administrations of LPS at intervals of 4 days after tumor inoculation inhibited liver metastasis of L5178Y-ML25 cells, whereas 3 consecutive i.v. administrations of LPS showed only a slight suppressive effect. Multiple i.v. administrations of LPS, synthetic lipid A, its synthetic derivative DT-5461, Staphylococcus aureus (S. aureus) BioParticles or Staphylococcal enterotoxin B (SEB) on days 1, 5 and 9 after tumor inoculation inhibited liver metastasis of T-lymphoma cells in normal mice. The anti-metastatic effects of LPS, synthetic lipid A or DT-5461 but not S. aureus BioParticles or SEB were diminished in mice injected with LPS at daily intervals for 7 days before tumor inoculation. Mice receiving 3 consecutive i.v. administrations of LPS at daily intervals exhibited suppression of LPS-induced production of endogenous tumor necrosis factor-alpha (TNF-alpha), tumoricidal activity of macrophages, and natural-killer (NK) activity of splenocytes when compared with those of normal mice. Macrophages from mice receiving consecutive daily i.v. administrations of LPS for 3 days showed reduction of LPS-induced tyrosine phosphorylation of several intracellular proteins, including p42(mapk) /ERK2 when compared with that of the cells obtained from normal mice. These data suggest that the LPS-induced anergic state of monocytes/macrophages plays a crucial role in endotoxin tolerance with respect to the metastasis of T lymphoma in the liver.
Sato
K
K
Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Yoo
Y C
YC
Matsuzawa
K
K
Watanabe
R
R
Saiki
I
I
Tono-Oka
S
S
Azuma
I
I
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004334:Drug Administration Schedule; D007111:Immunity, Cellular / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000556:secondary*; D016399:Lymphoma, T-Cell / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009362:Neoplasm Metastasis; D019000:Phosphotyrosine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019000:Phosphotyrosine