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Long-term suppression of tumor growth by TNF requires a Stat1- and IFN regulatory factor 1-dependent IFN-γ pathway but not IL-12 or IL-18

Item Type:Article
Title:Long-term suppression of tumor growth by TNF requires a Stat1- and IFN regulatory factor 1-dependent IFN-γ pathway but not IL-12 or IL-18
Creators Name:Wu, T.H. and Pabin, C.N. and Qin, Z.H. and Blankenstein, T. and Philip, M. and Dignam, J. and Schreiber, K. and Schreiber, H.
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} 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.
Keywords:B-Lymphocytes, Bone Marrow Transplantation, DNA-Binding Proteins, Experimental Neoplasms, Gene Silencing, Growth Inhibitors, Inbred C57BL Mice, Interferon Receptors, Interferon Regulatory Factor-1, Interferon Type II, Interleukin-12, Interleukin-18, Knockout Mice, Lymphopenia, Messenger RNA, Natural Killer Cells, Nude Mice, Phosphoproteins, Signal Transduction, STAT1 Transcription Factor, T-Lymphocytes, Trans-Activators, Transfection, Tumor Necrosis Factor-Alpha, Tumor Cell Line, Animals, Mice
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:172
Number:5
Page Range:3243-3251
Date:1 January 2004
Official Publication:https://doi.org/10.4049/jimmunol.172.5.3243
PubMed:View item in PubMed

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