Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10.
The administration of murine TNF-alpha to colon (C)-26 bearing mice, significantly protects the host against the catabolic effects of the tumor. This effect of exogenous TNF-alpha can be primarily attributed to tumor lysis rather than to a direct anticachectic action. Murine peritoneal macrophages cultured with the C-26 line or with C-26 culture supernatant do not release TNF-alpha in response to LPS stimulation. The reduction in TNF-alpha levels is associated with a significant increase in IL-10 levels. Single cell suspension of freshly disaggregated C-26 tumor (which contains host macrophages), do not produce TNF-alpha but contain significant levels of PGE2 and IL-10. In contrast, PGE2 but not TNF-alpha or IL-10 can be detected in the C-26.IVX cell line that is used to generate tumors in vivo. Neutralizing anti IL-10 Ab but not isotype-matched Ab, significantly reverses the inhibitory effect of the tumor cells and their culture supernatant on macrophage TNF-alpha release. Additional evidence is presented to indicate that the C-26-derived inhibitory activity is related to PGE2. Taken together, these results support the hypothesis that tumor-derived PGE2 prevents tumor-infiltrating macrophages from producing TNF-alpha, in part by augmenting macrophage IL-10 synthesis.
Kambayashi
T
T
Department of Immunology Otsuka-America Pharmaceutical Inc., Rockville, MD 20850.
Alexander
H R
HR
Fong
M
M
Strassmann
G
G
D000818:Animals; D000911:Antibodies, Monoclonal; D002100:Cachexia / Q000276:immunology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000276:immunology*; D017077:Culture Media, Conditioned; D015232:Dinoprostone / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D016753:Interleukin-10 / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015232:Dinoprostone