TUMOR-INDUCED REGULATION OF SUPPRESSOR MACROPHAGE NITRIC-OXIDE AND TNF-ALPHA PRODUCTION - ROLE OF TUMOR-DERIVED IL-10, TGF-BETA, AND PROSTAGLANDIN E(2)

In vitro-activated macrophages (M phi) co-express cytotoxicity for tum or cells and suppression of lymphocyte proliferation. These M phi func tions increase during tumor growth and are mediated by soluble molecul es. Because M phi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Met h-KDE) growth increased M phi-mediated suppression of T cell prolifera tion by increasing M phi NO and TNF-alpha production. Tumor-bearing ho st peritoneal M phi produced more NO and TNF-alpha than normal host M phi when activated with IFN-gamma or LPS, respectively. This tumor-ind uced increase in M phi NO and TNF-alpha production mediated suppressio n of alloantigen-driven T cell proliferation, because treatment with e ither N-G-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bea ring host M phi-mediated suppression. TNF-alpha did not directly suppr ess T cells, but it induced M phi NO production that down-regulated pr oliferation. When non-tumor-infiltrating peritoneal M phi were culture d with Meth-KDE cell supernatants, M phi production of NO and TNF-alph a was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta(1), and prostaglandin E(2). The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Reco mbinant forms of these cytokines suppressed NO and TNF-alpha productio n. 3) Ab-mediated absorption of these cytokines from tumor cell supern atants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TG F-beta(1), Ab addition to IFN-gamma-stimulated M phi restored NO produ ction. Culture supernatants of two human carcinoma cell lines and anot her murine fibrosarcoma suppressed M phi NO and TNF-alpha production, which was partly mediated by TGF-beta(1) and prostaglandin E(2). Colle ctively, these results suggest that tumor growth promotes distal M phi suppressor activity by increasing M phi production of cytotoxic molec ules and concomitantly down-regulating the local production of these a ntitumor molecules.