Interferon-gamma reduces tumor-induced Ia- macrophage-mediated suppression: role of prostaglandin E2, Ia, and tumor necrosis factor-alpha

Abstract

Tumor growth enhances macrophage (M phi) suppressor activity by causing M phi to increase synthesis of inhibitory molecules such as prostaglandin E2 (PGE2) or decreasing their expression of up-regulatory molecules such as the class II MHC protein Ia. Although these tumor-induced changes are correlated, it is unknown whether tumor-bearing host (TBH) Ia- M phi become more suppressive by increasing their PGE2 synthesis. To assess the role of PGE2 in tumor-induced Ia- M phi-mediated suppression of CD4+ T-cell alloreactivity, unseparated (Ia(+)-enriched) or Ia(+)-depleted (Ia-) populations of murine normal host (NH) or TBH splenic M phi were added to mixed lymphocyte reaction (MLR) cultures. NH or TBH Ia- M phi were significantly more suppressive than their respective unseparated populations, and TBH Ia- M phi were more suppressive than their NH counterparts. When PGE2 production was blocked with indomethacin, TBH Ia- M phi-mediated suppression was reduced more than suppression mediated by all other M phi populations. A PGE2-specific ELISA showed more PGE2 in Ia- M phi-containing cultures than in those with whole M phi and more in cultures containing TBH Ia- M phi than in their NH counterparts. Because interferon-gamma (IFN-gamma) is a potent M phi activation molecule that regulates both Ia expression and PGE2 production, the effects of IFN-gamma on tumor-induced Ia- M phi-mediated suppression were investigated. Exogenous IFN-gamma reduced suppression mediated by all M phi populations except NH unseparated M phi. IFN-gamma suppressed alloreactivity without M phi or with NH unseparated M phi. Suppression mediated by NH or TBH Ia-, and TBH unseparated M phi was also reduced when M phi were pre-incubated with IFN-gamma before their addition to MLR cultures. IFN-gamma addition did not block Ia- M phi-mediated suppression by decreasing M phi PGE2 production. In fact, IFN-gamma addition increased PGE2 production two-fold in MLR cultures. However, IFN-gamma partly reduced suppression mediated by exogenous PGE2 added to M phi-depleted cultures. Cytofluorometric analysis showed that IFN-gamma increased the percentage of Ia+ M phi in NH and TBH Ia- M phi populations. Blocking TNF-alpha activity with anti-TNF-alpha antibodies caused IFN-gamma to suppress alloreactivity in all M phi-added cultures. Collectively, these data show that tumor-induced suppression mediated by Ia- M phi is caused by increased PGE2 synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)