Tumor growth increases Ia- macrophage synthesis of tumor necrosis factor-alpha and prostaglandin E2: changes in macrophage suppressor activity.

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