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. 2002 Nov;110(10):1503-13.
doi: 10.1172/JCI15841.

Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS

Feng Hong  1 , Barbara Jaruga, Won Ho Kim, Svetlana Radaeva, Osama N El-Assal, Zhigang Tian, Van-Anh Nguyen, Bin Gao
Affiliations

Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS

Feng Hong et al. J Clin Invest. 2002 Nov.

Abstract

T cell-mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell-mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4(+) and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-gamma-deficient mice indicate that IFN-gamma not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6-deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A-mediated hepatitis by activation of CD4(+) and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-gamma signaling and induction of antiapoptotic protein Bcl-X(L). STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.

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Figures

Figure 1
Figure 1
Activation of multiple JAKs, STATs, SOCS, and apoptosis-associated proteins in the liver after injection of Con A. (a) and (b) C57BL/6J mice were injected with Con A (10 μg/g) at various time points. Total liver protein extracts and RNA were prepared and analyzed by Western blotting and RT-PCR (indicated by asterisks), respectively, using Ab’s and primers as indicated. Data are representative of three independent experiments with similar results. p, phosphorylated form.
Figure 2
Figure 2
Liver injury and STAT1 and SOCS1 activation are attenuated, but STAT3 and SOCS3 activation are enhanced and prolonged in Con A–induced hepatitis in STAT1–/– mice. (a) Mice were injected with 22 μg/g of Con A. At various time points, serum ALT levels were measured. Values are shown as means ± SEM from four mice at each time point. (b) Photomicrographs of representative mouse livers from 9-hour Con A–treated wild-type and STAT1–/– mice with H&E staining are shown (original magnification ×200 and ×400). White arrows indicate massive necrosis observed in the liver. (c) Wild-type control and STAT1–/– mice were injected with Con A (22 μg/g). At various time points after injection, serum was collected, and circulating IFN-γ levels were measured by ELISA. Values are shown as means ± SEM from three mice at each time point. (d) Total liver protein extracts and RNA from Con A–treated STAT1+/+ and STAT1–/– mice were analyzed by Western blotting and RT-PCR (indicated by asterisks), respectively, using Ab’s and primers as indicated. Induction of pSTAT1, pSTAT3, IRF-1, Bcl-XL, SOCS1, and SOCS3 was quantified by PhosphorImager analysis (left panel), as described in Methods. The values are shown as means ± SEM from four independent experiments at each time point. *P < 0.001, #P < 0.01 vs. corresponding Con A–treated wild-type control groups at the same time points.
Figure 3
Figure 3
IFN-γ and IL-6 induce prolonged activation of STAT3 in STAT1–/– mouse hepatocytes. Primary cultured mouse hepatocytes were treated with IFN-γ (10 ng/ml) or IL-6 (20 ng/ml). At various time points, as indicated, cell protein extracts and RNA were prepared and analyzed by Western blotting and RT-PCR (indicated by asterisks), respectively, using Ab’s or primers as indicated. Similar data were obtained from five independent experiments.
Figure 4
Figure 4
Liver injury, STAT1 and SOCS1 activation are attenuated, whereas STAT3 activation is slightly enhanced in Con A–induced hepatitis in IFN-γ–/– mice. (a) IFN-γ+/+ mice and IFN-γ–/– mice were injected with 15 μg/g of Con A. At various time points, total liver protein extracts and RNA were prepared and analyzed by Western blotting and RT-PCR (indicated by asterisks), respectively, using Ab’s and primers as indicated. Induction of pSTAT1, pSTAT3, IRF-1, Bcl-XL, SOCS1, and SOCS3 was quantified by PhosphorImager analysis (left panel), as described in Methods. The values are shown as means ± SEM from three independent experiments at each time point. *P < 0.001, #P < 0.01, and §P < 0.05 vs. corresponding Con A–treated wild-type control groups at the same time point. (b) Serum ALT levels from these mice were measured. Values shown as means ± SEM from three mice at each time point. (c) Photomicrographs of representative mouse livers from 9-hour Con A–treated mice with H&E staining are shown (original magnification ×200 and ×400). White arrows indicate massive necrosis observed in the liver.
Figure 5
Figure 5
STAT3 and SOCS3 activation are attenuated, but liver injury, STAT1, IRF-1, and SOCS1 activation are enhanced in Con A–induced hepatitis in IL-6–/– mice. (a) IL-6+/+ mice and IL-6–/– mice were injected with 10 μg/g of Con A. At various time points, liver protein extracts and RNA were analyzed by Western blot or RT-PCR (indicated by asterisks), respectively, using Ab’s and primers as indicated (left panel), and quantified by PhosphorImager analysis (right panel). The values are shown as means ± SEM from four independent experiments. *P < 0.001, #P < 0.01, §P < 0.05 vs. corresponding control groups at the same time point. (b) Serum ALT levels from these mice were measured. Values are shown as means ± SEM from four mice at each time point. (c) Photomicrographs of representative mouse livers obtained 9 hours after Con A injection with H&E staining are shown (original magnification ×200 and ×400). White arrows indicate massive necrosis observed in the liver. (d) Wild-type control and IL-6–/– mice were injected with Con A (10 μg/g). At various time points, serum IFN-γ levels were measured. Values are shown as means ± SEM from three mice at each time point. *P < 0.001 vs. corresponding Con A-treated wild-type control groups at the same time points. (e) C57BL/6J mice were injected (intravenously) with IL-6 (2 μg/g), followed 6 hours later by injection of Con A (10 μg/g). After 8 hours, serum ALT levels were measured. Values shown are means ± SEM from five mice. Significant difference from corresponding Con A–treated group is indicated by asterisks. *P < 0.01.
Figure 6
Figure 6
Con A injection–mediated activation of CD4+ and NK T cells is abolished in STAT1–/– and IFN-γ–/– but not in IL-6–/– mice. Wild-type and knockout mice were injected with Con A for 3, 6, and 9 hours. Hepatic lymphocytes were isolated. The surface of CD4+CD69+ or NK1.1+CD3+ was analyzed by flow cytometry. The flow cytometric analysis is representative of three independent experiments. The upper-right quadrant in each panel shows CD3+CD69+ or NK1.1+CD3+ double-positive cells (percentage of the total hepatic lymphocytes). Values are shown in d as means ± SEM from three mice at each time point. *P < 0.001 and #P < 0.01 vs. corresponding Con A–treated wild-type groups at the same time points.
Figure 7
Figure 7
A model illustrating opposing roles of STAT1 and STAT3 in Con A–induced hepatitis. Con A activates multiple immune cells, including NK T cells and CD4+ T cells, and induces the release of a variety of cytokines. IFN-γ induces activation of JAK1 and JAK2 and consequent activation of STAT1. IFN-γ/STAT1 play an essential role in CD4+ and NK T cell activation, which, in turn, directly or indirectly induce liver injury. IFN-γ/STAT1 also induce expression of proapoptotic IRF-1 protein, which mediates liver apoptosis and injury. IL-6 and IFN-γ activate JAK1 and JAK2 and consequently induce STAT3 activation, followed by induction of Bcl-XL and other antiapoptotic factors, which protect against hepatic necrosis and apoptosis. IL-6 activation of STAT3 also downregulates IFN-γ and IFN-γ signaling and consequently suppresses IFN-γ/STAT1-induced liver injury. Activated STAT1 and STAT3 inhibit one another, at least in hepatocytes, by the induction of SOCS.
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