Interleukin-2 suppresses activated macrophage intracellular killing activity by inducing macrophages to secrete TGF-beta

• Published in: Journal of leukocyte biology 1994-01, Vol.55 (1), p.81-90
• Main Authors: Nelson, Barbara J., Danielpour, David, Rossio, Jeffrey L., Turpin, Jim, Nacy, Carol A.
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Biological and medical sciences; Cell interactions; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunobiology; Interferon-gamma - pharmacology; interferon‐γ; Interleukin-2 - pharmacology; interleukin‐2; intracellular killing; Leishmania; Leishmania major - immunology; Macrophage Activation - drug effects; macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Receptors, Interleukin-2 - analysis; suppression; Tetradecanoylphorbol Acetate - pharmacology; Transforming Growth Factor beta - biosynthesis; transforming growth factor β; Tumor Cells, Cultured
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1002/jlb.55.1.81

Phorbol myristate acetate (PMA) treatment of an EL‐4 thymoma cell line (EL‐4farrar) induced secretion of a factor that inhibited intracellular killing of Leishmania major amastigotes by activated macrophages. Analysis of the cytokines produced by EL‐4 cells after PMA stimulation identified interleukin‐2 (IL‐2, 2500 U/ml), IL‐4 (1280 U/ml), interferon‐γ (IFN‐γ; 100 U/ml), and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF; 50 U/ml). Neither tumor necrosis factor nor transforming growth factor β (TGF‐β) was detected. Each of the cytokines present in EL‐4 fluids was assessed for capacity to activate macrophages for destruction of parasites or to suppress intracellular killing. IFN‐γ and GM‐CSF both activated macrophages to kill Leishmania; I L‐2 and IL‐4 had no activity for induction of this anti‐microbial effector function. IL‐2 and IL‐4 were tested for their capacity to inhibit lymphokine‐ or IFN‐γ‐induced destruction of L. major by macrophages: IL‐4 was ineffective, but IL‐2 markedly suppressed the activation of macrophages for intracellular killing. Addition of ≥ 10 U/ml of IL‐2 at the time of infection, or up to 4 h before, blocked up to 100% of the capacity of activated macrophages to kill intracellular amastigotes. Immunoaffinity treatment of EL‐4 fluids with anti‐IL‐2 antibody resulted in >80% reduction in suppression of intracellular killing. The suppressive effects of IL‐2 were not direct, but mediated by TGF‐β. IL‐2 induced resident peritoneal macrophages to secrete >5000 pg/ml TGF‐β1, a quantity that is > 500‐fold higher than constitutive background levels (20–40 pg/ml) and is sufficient to block intracellular killing activities. This increase in secretion of TGF‐β was not dependent increases in TGF‐β1 mRNA. Treatment of cultures with EL‐4 fluids or recombinant IL‐2 in the presence of antibody to TGF‐β1 blocked the suppressive activity of both. Thus, IL‐2 was the major suppressor factor in EL‐4 fluids, and it acted indirectly through the induction and autocrine action of TGF‐β. J. Leukoc. Biol. 55: 81–90; 1994.