Prostaglandin E 2 Production by Mac‐2 + Macrophages: Tumor‐Induced Population Shift

Tumor growth induced a shift in the phenotype of macrophages (MΦ) responsible for factor‐mediated suppression of allogeneic mixed lymphocyte reactions (MLR), and the suppression by tumor‐bearing host (TBH) Mac‐2 + MΦ was in part due to production of prostaglandin E 2 (PGE 2 ). Thioglycollate‐elicited peritoneal MΦ from normal and TBH BALB/c mice were modulated with anti‐Mac‐1, ‐2, or ‐3 monoclonal antibodies (mAb) or depleted with mAb plus complement and cultured in the presence or absence of indomethacin. Culture supernatants derived from mAb plus complement‐depleted Mo were added to the MLR at time of initiation and showed that the suppressor phenotype shifted from Mac‐3 + in the normal host to Mac‐2 + in the TBH. Mac‐1 + MΦ also appeared to be involved in suppression by normal host, but not TBH, MΦ. Loss of MLR suppression (increase in MLR reactivity) correlated with an increase in protein content of the culture supernatants. In an effort to explain both this relationship and the mechanism of MLR suppression, PGE 2 levels of culture supernatants were determined by radioimmunoassay. Mac‐1 + MΦ were involved in the regulation of PGE 2 production in normal hosts, as both activation and depletion caused an increase in PGE 2 production. Depletion caused a more dramatic increase in PGE 2 production than did activation, suggesting that Mac‐1 + MΦ had a dampening effect on PGE 2 production. In contrast, no Mac‐1 + MΦ‐mediated regulatory function occurred in the TBH. Mac‐3 + MΦ were involved in the regulation of PGE 2 production in both normal and TBH. Mac‐2 + MΦ were the primary producers of PGE 2 in the TBH, but not in the normal host, as their depletion in the TBH caused a significant loss of PGE 2 production. Thus, immunosuppression in the TBH was at least partly due to the inability of Mac‐1 + and/or Mac‐3 + MΦ to control production of PGE 2 by Mac‐2 + MΦ.