Induction of macrophage suppressor activity by fibrosarcoma-derived transforming growth factor-beta 1: contrasting effects on resting and activated macrophages.

Tumor-derived transforming growth factor-beta 1 (TGF-beta 1) suppresses several immune responses. Because tumor growth induces macrophage (m phi) suppressor activity, we determined whether murine fibrosarcoma-derived TGF-beta 1 contributed to m phi-mediated suppression of autoantigen- and alloantigen-stimulated T cell proliferation. The murine fibrosarcoma Meth-KDE cell line constitutively produced TGF-beta 1. Meth-KDE tumor-bearing host (TBH) syngeneic splenic m phi s suppressed autoantigen- and alloantigen-stimulated normal host (NH) CD4+ T cell proliferation. Pretreatment with Meth-KDE supernatants induced NH m phi s to suppress T cell proliferation as much as TBH m phi s. Anti-TGF-beta 1 antibody treatment reversed Meth-KDE-induced NH m phi-mediated suppression. Recombinant TGF-beta 1-induced m phi-mediated suppression was not blocked during inhibition of prostaglandin E2 (PGE2), nitric oxide (NO), or TGF-beta 1 production. However, Meth-KDE-induced m phi-mediated suppression was partly reduced when PGE2 production was inhibited. Pretreatment with tumor cell-derived TGF-beta 1, but not recombinant TGF-beta 1, increased activated m phi PGE2 production. These results show that additional tumor-derived molecules aid in TGF-beta 1-enhanced PGE2 production. Also, TGF-beta 1 alone up-regulates m phi synthesis of suppressor molecules that are different from PGE2, NO, and TGF-beta 1. Although TGF-beta 1 has direct suppressor activity on lymphocytes, these results show that release of tumor cell TGF-beta 1 also induces m phi suppressor activity.