Tumor growth increases la − macrophage synthesis of tumor necrosis factor‐α and prostaglandin E2: changes in macrophage suppressor activity

Although tumor growth enhances macrophage (mφ) cytotoxic activity by increasing their tumor necrosis factor‐a (TNF‐a) production, increased prostaglandin E 2 (PGE2) synthesis reduces most immune responses during tumor growth. Macrophages that do not express major histocompatibility complex class II molecules (la − mφ) are the predominant suppressor and cytotoxic population and are more abundant in tumor‐bearing hosts (TBHs). This study determined if TBH la' mφs are the major population producing TNF‐α and PGE2 and if these molecules affect la' mφ‐mediated suppression of alloantigen‐stimulated T cell proliferation. Normal host (NH) and TBH splenic Ia + ‐depleted (la − ) mφs synthesized more TNF‐a than their respective whole populations (WPs) when cultured with lipopolysaccharide and interferon‐7. TBH la' mφs produced the most TNF‐α. Northern blot analyses showed that la' mφs had higher amounts of TNF‐α mRNA expression than their respective WP, and TBH la” mφs expressed the highest amounts of TNF‐α mRNA. When WP and la' NH and TBH mφs were added to alloantigen‐stimulated T cells, suppression of T cell proliferation mediated by la' m φ s was greater than by their respective WP. TBH Ia − mφs were most suppressive. The blockage of PGE2 production reduced suppression mediated by TBH la” mφs more than by all other m φ populations. A PGE2‐specific enzyme‐linked immunosorbent assay showed that PGE2 production was greater in la' mφ‐ than in WP mφ‐containing cultures and greatest in cultures containing TBH la' mφs. Because TNF‐α enhances T cell responses, its effects on la'mφ PGE2‐mediated suppression was determined. When TNF‐ a was added to mφ‐containing T cell cultures, TNF‐α directly stimulated NH, but not TBH, la' mφs, which enhanced T cell proliferation. However, inhibiting PGE2 production allowed TNF‐a to stimulate T cell proliferation in TBH la” mφ‐containing cultures. Collectively, these data show that la' mφs are the major TNF‐α‐ and PGE2‐producing cells and that these molecules are partly responsible for the tumor‐induced increase in mφ‐ mediated cytotoxicity and suppression, respectively. TNFα not only mediates cytotoxicity but also counteracts la − mφ PGE2‐mediated suppression. Although tumor growth increases la' m φ TNF‐α production, enhanced PGE2 production blocks TNF‐α's stimulatory action on la” mφs, which favors their suppressor function during tumor growth.