Abstract
Tumor cells engineered to secrete TNF were used as a model to examine how persistently high local concentrations of TNF suppress tumor growth. TNF secretion had no effect on tumor cell proliferation in vitro but caused a very impressive growth arrest in vivo that was dependent on both bone marrow- and non-bone marrow-derived host cells expressing TNFR. Suppression also required an endogenous IFN-gamma pathway consisting minimally of IFN-gamma, IFN-gamma receptor, Stat1, and IFN regulatory factor 1 since mice with targeted disruption of any of the four genes failed to arrest tumor growth. The ability of these mice to suppress tumor growth was restored after they were reconstituted with bone marrow cells from Wt mice. Interestingly, mice lacking the major IFN-gamma-inducing cytokines IL-12 and IL-18 or T cells, B cells, and the majority of NK cells that are potential sources of IFN-gamma nevertheless inhibited tumor development. Moreover, multiple lines of evidence indicated that local release of IFN-gamma was not required to inhibit tumor formation. These results strongly suggest a novel function for the endogenous IFN-gamma pathway that without measurable IFN-gamma production or activity affects the ability of TNF to suppress tumor development.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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B-Lymphocytes / pathology
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Bone Marrow Transplantation / immunology
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Cell Line, Tumor
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DNA-Binding Proteins / physiology*
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Gene Silencing
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Growth Inhibitors / genetics
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Growth Inhibitors / metabolism
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Growth Inhibitors / pharmacology*
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Humans
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Interferon Regulatory Factor-1
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Interferon gamma Receptor
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / physiology*
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Interleukin-12 / physiology
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Interleukin-18 / physiology
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Killer Cells, Natural / pathology
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Lymphopenia / genetics
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Lymphopenia / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Nude
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / immunology*
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Neoplasms, Experimental / pathology
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Phosphoproteins / physiology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Interferon / deficiency
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Receptors, Interferon / genetics
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STAT1 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes / pathology
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Trans-Activators / physiology*
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Transfection
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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DNA-Binding Proteins
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Growth Inhibitors
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IRF1 protein, human
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Interferon Regulatory Factor-1
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Interleukin-18
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Irf1 protein, mouse
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Phosphoproteins
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RNA, Messenger
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Receptors, Interferon
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STAT1 Transcription Factor
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STAT1 protein, human
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Stat1 protein, mouse
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Trans-Activators
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Interferon-gamma