POTENTIAL INVOLVEMENT OF IL-10 IN SUPPRESSING TUMOR-ASSOCIATED MACROPHAGES - COLON-26-DERIVED PROSTAGLANDIN E(2) INHIBITS TNF-ALPHA RELEASEVIA A MECHANISM INVOLVING IL-10

The administration of murine TNF-alpha to colon (C)-26 bearing mice, s ignificantly protects the host against the catabolic effects of the tu mor. This effect of exogenous TNF-alpha can be primarily attributed to tumor lysis rather than to a direct anticachectic action. Murine peri toneal macrophages cultured with the C-26 line or with C-26 culture su pernatant do not release TNF-alpha in response to LPS stimulation. The reduction in TNF-alpha levels is associated with a significant increa se in IL-10 levels. Single cell suspension of freshly disaggregated C- 26 tumor (which contains host macrophages), do not produce TNF-alpha b ut 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 bu t not isotype-matched Ab, significantly reverses the inhibitory effect of the tumor cells and their culture supernatant on macrophage TNF-al pha release. Additional evidence is presented to indicate that the C-2 6-derived inhibitory activity is related to PGE(2). Taken together, th ese results support the hypothesis that tumor-derived PGE(2) prevents tumor-infiltrating macrophages from producing TNF-alpha, in part by au gmenting macrophage IL-10 synthesis.