Chronic inflammatory IFN-γ signaling suppresses hepatocarcinogenesis in mice by sensitizing hepatocytes for apoptosis.
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Chronic inflammatory IFN-γ signaling suppresses hepatocarcinogenesis in mice by sensitizing hepatocytes for apoptosis. / Lüth, Stefan; Schrader, Jörg; Zander, Stefan; Carambia, Antonella; Buchkremer, Juliane; Huber, Samuel; Reifenberg, Kurt; Yamamura, Ken-Ichi; Schirmacher, Peter; Lohse, Ansgar W.; Herkel, Johannes.
In: CANCER RES, Vol. 71, No. 11, 11, 2011, p. 3763-3771.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Chronic inflammatory IFN-γ signaling suppresses hepatocarcinogenesis in mice by sensitizing hepatocytes for apoptosis.
AU - Lüth, Stefan
AU - Schrader, Jörg
AU - Zander, Stefan
AU - Carambia, Antonella
AU - Buchkremer, Juliane
AU - Huber, Samuel
AU - Reifenberg, Kurt
AU - Yamamura, Ken-Ichi
AU - Schirmacher, Peter
AU - Lohse, Ansgar W.
AU - Herkel, Johannes
PY - 2011
Y1 - 2011
N2 - Chronic liver inflammation is a critical component of hepatocarcinogenesis. Indeed, inflammatory mediators are believed to promote liver cancer by upholding compensatory proliferation of hepatocytes in response to tissue damage. However, inflammation can also mediate the depletion of malignant cells, but the difference between tumor-suppressive and tumor-promoting inflammation is not defined at the molecular level. Here, we analyzed the role of the major inflammatory mediator IFN-? in chemical hepatocarcinogenesis of transgenic mice that overexpress IFN-? in the liver; these mice manifest severe chronic inflammatory liver damage and lasting compensatory regeneration. We found that chronic exposure to IFN-? suppressed chemical hepatocarcinogenesis, despite overt liver injury. Indeed, IFN-?-transgenic mice had significantly fewer and significantly less advanced malignant lesions than nontransgenic mice. This tumor-suppressive effect of IFN-? seemed to be mediated in part by its known immune activating function, indicated by infiltration of IFN-?-transgenic livers with CD8 T cells, natural killer T cells, and natural killer cells. However, IFN-? seemed to prevent carcinogenesis also by activating the cell-intrinsic p53 tumor suppressor pathway. Indeed, exposure to IFN-? in vivo or in vitro was associated with accumulation of p53 in hepatocytes and the sensitization of hepatocytes to apoptosis induced by genotoxic stress. The IFN-?-induced increase in apoptosis of hepatocytes seemed to be p53 dependent. Thus, chronic inflammation dominated by IFN-? may prevent hepatocarcinogenesis, despite continued inflammatory liver injury and regeneration. Therefore, the carcinogenic potential of inflammation seems to be determined by type and composition of its mediators and manipulating the type of chronic inflammation may serve the prevention of cancer.
AB - Chronic liver inflammation is a critical component of hepatocarcinogenesis. Indeed, inflammatory mediators are believed to promote liver cancer by upholding compensatory proliferation of hepatocytes in response to tissue damage. However, inflammation can also mediate the depletion of malignant cells, but the difference between tumor-suppressive and tumor-promoting inflammation is not defined at the molecular level. Here, we analyzed the role of the major inflammatory mediator IFN-? in chemical hepatocarcinogenesis of transgenic mice that overexpress IFN-? in the liver; these mice manifest severe chronic inflammatory liver damage and lasting compensatory regeneration. We found that chronic exposure to IFN-? suppressed chemical hepatocarcinogenesis, despite overt liver injury. Indeed, IFN-?-transgenic mice had significantly fewer and significantly less advanced malignant lesions than nontransgenic mice. This tumor-suppressive effect of IFN-? seemed to be mediated in part by its known immune activating function, indicated by infiltration of IFN-?-transgenic livers with CD8 T cells, natural killer T cells, and natural killer cells. However, IFN-? seemed to prevent carcinogenesis also by activating the cell-intrinsic p53 tumor suppressor pathway. Indeed, exposure to IFN-? in vivo or in vitro was associated with accumulation of p53 in hepatocytes and the sensitization of hepatocytes to apoptosis induced by genotoxic stress. The IFN-?-induced increase in apoptosis of hepatocytes seemed to be p53 dependent. Thus, chronic inflammation dominated by IFN-? may prevent hepatocarcinogenesis, despite continued inflammatory liver injury and regeneration. Therefore, the carcinogenic potential of inflammation seems to be determined by type and composition of its mediators and manipulating the type of chronic inflammation may serve the prevention of cancer.
KW - Animals
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Signal Transduction
KW - Mice, Transgenic
KW - Apoptosis/drug effects
KW - Cell Transformation, Neoplastic/drug effects/immunology/pathology
KW - Hepatocytes/drug effects/immunology/metabolism
KW - Inflammation/immunology/pathology
KW - Inflammation Mediators/immunology
KW - Interferon-gamma/immunology/pharmacology
KW - Liver/drug effects/immunology/metabolism
KW - Liver Neoplasms, Experimental/immunology/pathology
KW - T-Lymphocytes/metabolism
KW - Tumor Suppressor Protein p53/metabolism
KW - Animals
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Signal Transduction
KW - Mice, Transgenic
KW - Apoptosis/drug effects
KW - Cell Transformation, Neoplastic/drug effects/immunology/pathology
KW - Hepatocytes/drug effects/immunology/metabolism
KW - Inflammation/immunology/pathology
KW - Inflammation Mediators/immunology
KW - Interferon-gamma/immunology/pharmacology
KW - Liver/drug effects/immunology/metabolism
KW - Liver Neoplasms, Experimental/immunology/pathology
KW - T-Lymphocytes/metabolism
KW - Tumor Suppressor Protein p53/metabolism
M3 - SCORING: Journal article
VL - 71
SP - 3763
EP - 3771
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 11
M1 - 11
ER -
