Although tumor growth enhances macrophage (mphi) cytotoxic activity by increasing their tumor necrosis factor-alpha (TNF-alpha) production, increased prostaglandin E2 (PGE2) synthesis reduces most immune responses during tumor growth. Macrophages that do not express major histocompatibility complex class II molecules (Ia- mphi) are the predominant suppressor and cytotoxic population and are more abundant in tumor-bearing hosts (TBHs). This study determined if TBH Ia- mphis are the major population producing TNF-alpha and PGE2 and if these molecules affect Ia- mphi-mediated suppression of alloantigen-stimulated T cell proliferation. Normal host (NH) and TBH splenic Ia+-depleted (Ia-) mphis synthesized more TNF-alpha than their respective whole populations (WPs) when cultured with lipopolysaccharide and interferon-gamma. TBH Ia- mphis produced the most TNF-alpha. Northern blot analyses showed that Ia- mphis had higher amounts of TNF-alpha mRNA expression than their respective WP, and TBH Ia- mphis expressed the highest amounts of TNF-alpha mRNA. When WP and Ia- NH and TBH mphis were added to alloantigen-stimulated T cells, suppression of T cell proliferation mediated by Ia- mphis was greater than by their respective WP. TBH Ia- mphis were most suppressive. The blockage of PGE2 production reduced suppression mediated by TBH Ia- mphis more than by all other mphi populations. A PGE2-specific enzyme-linked immunosorbent assay showed that PGE, production was greater in Ia- mphi- than in WP mphi-containing cultures and greatest in cultures containing TBH Ia- mphis. Because TNF-alpha enhances T cell responses, its effects on Ia- mphi PGE2-mediated suppression was determined. When TNF-alpha was added to mphi-containing T cell cultures, TNF-alpha directly stimulated NH, but not TBH, Ia- mphis, which enhanced T cell proliferation. However, inhibiting PGE2 production allowed TNF-alpha to stimulate T cell proliferation in TBH Ia- mphi-containing cultures. Collectively, these data show that Ia- mphis are the major TNF-alpha- and PGE2-producing cells and that these molecules are partly responsible for the tumor-induced increase in mphi-mediated cytotoxicity and suppression, respectively. TNF-alpha not only mediates cytotoxicity but also counteracts Ia- mphi PGE2-mediated suppression. Although tumor growth increases Ia- mphi TNF-alpha production, enhanced PGE2 production blocks TNF-alpha's stimulatory action on Ia- mphis, which favors their suppressor function during tumor growth.
