Tumor-induced regulation of suppressor macrophage nitric oxide and TNF- alpha production. Role of tumor-derived IL-10, TGF-beta, and prostaglandin E2

• Published in: The Journal of immunology (1950) Vol. 153; no. 4; pp. 1674 - 1686
• Main Authors: Alleva, DG, Burger, CJ, Elgert, KD
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.08.1994
• Subjects: Animals; Cytotoxicity, Immunologic; Dinoprostone - physiology; Immunity, Cellular; Immunosuppressive Agents; Interleukin-10 - physiology; Lymphocyte Activation; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Nitric Oxide - metabolism; Sarcoma, Experimental - immunology; T-Lymphocytes - immunology; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - physiology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.153.4.1674

In vitro-activated macrophages (Mphi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These Mphi functions increase during tumor growth and are mediated by soluble molecules. Because Mphi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased Mphi-mediated suppression of T cell proliferation by increasing Mphi NO and TNF-alpha production. Tumor-bearing host peritoneal Mphi produced more NO and TNF-alpha than normal host Mphi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in Mphi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either NG-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host Mphi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced Mphi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal Mphi were cultured with Meth-KDE cell supernatants, Mphi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta 1, and prostaglandin E2. The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta 1 Ab addition to IFN-gamma-stimulated Mphi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2. Collectively, these results suggest that tumor growth promotes distal Mphi suppressor activity by increasing Mphi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.