Fibrosarcoma-induced increase in macrophage tumor necrosis factor alpha synthesis suppresses T cell responses

Tumors down-regulate T cell responses partly by increasing macrophage (m phi) production of the suppressive molecule prostaglandin E2 (PGE2). Because tumor growth increases m phi tumor necrosis factor alpha (TNF-alpha) production and TNF-alpha stimulates m phi PGE2 synthesis, we examined the contribution of TNF-alpha to fibrosarcoma-induced m phi-mediated suppression of alloreactive CD4+ T cell proliferation. We showed that tumor-bearing host (TBH) m phi s express high levels of TNF-alpha mRNA, which leads to increased lipopolysaccharide-induced TNF-alpha production. Tumor cells were directly involved in m phi TNF-alpha synthesis because fibrosarcoma cells induced normal host (NH) m phi s to produce TNF-alpha. Addition of TBH m phi s to allogeneic mixed lymphocyte reaction (MLR) cultures suppressed CD4+ T cell proliferation more than NH m phi s. The neutralization of endogenous TNF-alpha activity with anti-TNF-alpha antibody (Ab) treatment reversed TBH, but not NH, m phi-mediated suppression. Conversely, exogenous TNF-alpha increased NH or TBH m phi-mediated suppression but stimulated T cell proliferation without m phi s. Kinetic treatment of MLR cultures with anti-TNF-alpha Ab or TNF-alpha showed that TNF-alpha production and activity occurred at the beginning of T cell proliferation. When arachidonic acid metabolite synthesis was inhibited, TNF-alpha-induced suppression was blocked in NH m phi-containing cultures and completely reversed in TBH m phi-containing cultures. A PGE2-specific enzyme-linked immunosorbent assay showed that TNF-alpha addition increased PGE2 production in NH m phi-containing cultures to that of TBH m phi-containing cultures. Exogenous PGE2 did not affect the TNF-alpha enhancement of T cell proliferation without m phi s. Therefore, suppression induced by TNF-alpha was caused by increased m phi 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 m phi s, the main TNF-alpha producers, TNF-alpha suppresses T cell proliferation. Perhaps increased TNF-alpha production during pathological states, such as cancer, triggers the initial stages of suppression.