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.
Alleva
D G
DG
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406, USA.
Walker
T M
TM
Elgert
K D
KD
D000818:Animals; D015232:Dinoprostone / Q000502:physiology; D005354:Fibrosarcoma / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011994:Recombinant Proteins / Q000494:pharmacology; D013491:Suppressor Factors, Immunologic / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology*
D011994:Recombinant Proteins; D013491:Suppressor Factors, Immunologic; D016212:Transforming Growth Factor beta; D015232:Dinoprostone