POTENTIAL INVOLVEMENT OF IL-10 IN SUPPRESSING TUMOR-ASSOCIATED MACROPHAGES - COLON-26-DERIVED PROSTAGLANDIN E(2) 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 PGE(2) and IL-10. In contrast, PGE(2) but not TNF-alpha or IL-70 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 PGE(2). Taken together, these results support the hypothesis that tumor-derived PGE(2) prevents tumor-infiltrating macrophages from producing TNF-alpha, in part by augmenting macrophage IL-10 synthesis.