FIBROSARCOMA-INDUCED INCREASE IN MACROPHAGE TUMOR-NECROSIS-FACTOR-ALPHA SYNTHESIS SUPPRESSES T-CELL RESPONSES

Tumors down-regulate T cell responses partly by increasing macrophage (mphi) production of the suppressive molecule prostaglandin E2 (PGE2). Because tumor growth increases mphi tumor necrosis factor alpha (TNF- alpha) production and TNF-alpha stimulates mphi PGE2 synthesis, we exa mined the contribution of TNF-alpha to fibrosarcoma-induced mphi-media ted suppression of allo-reactive CD4+ T cell proliferation. We showed that tumor-bearing host (TBH) mphis express high levels of TNF-alpha m RNA, which leads to increased lipopolysaccharide-induced TNF-alpha pro duction. Tumor cells were directly involved in mphi TNF-alpha synthesi s because fibrosarcoma cells induced normal host (NH) mphis to produce TNF-alpha. Addition of TBH mphis to allogeneic mixed lymphocyte react ion (MLR) cultures suppressed CD4+ T cell proliferation more than NH m phis. The neutralization of endogenous TNF-alpha activity with anti-TN F-alpha antibody (Ab) treatment reversed TBH, but not NH, mphi-mediate d suppression. Conversely, exogenous TNF-alpha increased NH or TBH mph i-mediated suppression but stimulated T cell proliferation without mph is. Kinetic treatment of MLR cultures with anti-TNF-alpha Ab or TNF-al pha showed that TNF-alpha production and activity occurred at the begi nning of T cell proliferation. When arachidonic acid metabolite synthe sis was inhibited, TNF-alpha-induced suppression was blocked in NH mph i-containing cultures and completely reversed in TBH mphi-containing c ultures. A PGE2-specific enzyme-linked immunosorbent assay showed that TNF-alpha addition increased PGE2 production in NH mphi-containing cu ltures to that of TBH mphi-containing cultures. Exogenous PGE2 did not affect the TNF-alpha enhancement of T cell proliferation without mphi s. Therefore, suppression induced by TNF-alpha was caused by increased mphi PGE2 Production and not by TNF-alpha in concert with PGE2. Even though TNF-alpha is known to enhance lymphocyte proliferation, we show that in the presence of mphis, the main TNF-alpha producers, TNF-alph a suppresses T cell proliferation. Perhaps increased TNF-alpha product ion during pathological states, such as cancer, triggers the initial s tages of suppression.