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CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.

Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A - J. Exp. Med. (2001)

Bottom Line: We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation.Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis.These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Life Science, Kurume University, Kurume 839-0861, Japan.

ABSTRACT
Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell-dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

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DSS-induced colitis in IL-6−/− and IFN-γ−/− mice. (A) Time course of body weight loss. WT C57BL6 mice or IL-6−/− or IFN-γ−/− mice (n = 3 for each knockout mice) were treated with 2% DSS for indicated periods, and body weight was measured daily. Relative body weight (%) compared with that of day 0 is plotted with a standard error. Results were analyzed using the t test. A P value of <0.05 was considered to be statistically significant. (B) Histological section of an ulcer with hematoxylin and eosin staining. Pathology was graded on a scale of 0–12. Data represent the average with SEM for the group. The average score for IL-6−/− mice, but not IFN-γ−/− mice, was significantly different from that for the WT mice (P = 0.013). Statistical analysis was performed using the t test. (C) STAT3 phosphorylation in the colon of WT and IL-6−/− mice treated with DSS. Colon tissue extracts from three independent mice of each strain were immunoblotted with anti–phospho-STAT3 (αPY-STAT3) and anti-STAT3 (αSTAT3) antibodies.
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Figure 2: DSS-induced colitis in IL-6−/− and IFN-γ−/− mice. (A) Time course of body weight loss. WT C57BL6 mice or IL-6−/− or IFN-γ−/− mice (n = 3 for each knockout mice) were treated with 2% DSS for indicated periods, and body weight was measured daily. Relative body weight (%) compared with that of day 0 is plotted with a standard error. Results were analyzed using the t test. A P value of <0.05 was considered to be statistically significant. (B) Histological section of an ulcer with hematoxylin and eosin staining. Pathology was graded on a scale of 0–12. Data represent the average with SEM for the group. The average score for IL-6−/− mice, but not IFN-γ−/− mice, was significantly different from that for the WT mice (P = 0.013). Statistical analysis was performed using the t test. (C) STAT3 phosphorylation in the colon of WT and IL-6−/− mice treated with DSS. Colon tissue extracts from three independent mice of each strain were immunoblotted with anti–phospho-STAT3 (αPY-STAT3) and anti-STAT3 (αSTAT3) antibodies.

Mentions: STAT3 has been shown to be mainly activated by IL-6–related cytokines, and the elevation of the IL-6 level has been reported in DSS-induced colitis. On the other hand, IFN-γ has been shown to activate mainly STAT1. For this reason, we investigated the role of STAT3 in the pathology of DSS-induced colitis using IL-6−/− and IFN-γ−/− mice in a C57BL/6 background (Fig. 2). All IL-6+/+ mice developed severe colitis characterized by loss of weight, marked epithelial hyperplasia, extensive leukocyte infiltration, and goblet cell depletion. Inflammatory infiltrates, which consisted mainly of mononuclear cells, were observed in the lamina propria in WT mice. These changes were not very obvious in IL-6−/− mice (Fig. 2a and Fig. b). On the other hand, IFN-γ–deficient mice developed colitis as severely as WT mice. Then, we compared STAT3 activation in WT and IL-6−/− mice. As shown in Fig. 2 C, STAT3 phosphorylation in the colon of WT mice was much more intensive than that in IL-6−/− mice. These data suggest that STAT3 activation in intestinal cells contributes to the development of colitis and constitutive activation of STAT3 may prevent healing of colitis.


CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.

Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A - J. Exp. Med. (2001)

DSS-induced colitis in IL-6−/− and IFN-γ−/− mice. (A) Time course of body weight loss. WT C57BL6 mice or IL-6−/− or IFN-γ−/− mice (n = 3 for each knockout mice) were treated with 2% DSS for indicated periods, and body weight was measured daily. Relative body weight (%) compared with that of day 0 is plotted with a standard error. Results were analyzed using the t test. A P value of <0.05 was considered to be statistically significant. (B) Histological section of an ulcer with hematoxylin and eosin staining. Pathology was graded on a scale of 0–12. Data represent the average with SEM for the group. The average score for IL-6−/− mice, but not IFN-γ−/− mice, was significantly different from that for the WT mice (P = 0.013). Statistical analysis was performed using the t test. (C) STAT3 phosphorylation in the colon of WT and IL-6−/− mice treated with DSS. Colon tissue extracts from three independent mice of each strain were immunoblotted with anti–phospho-STAT3 (αPY-STAT3) and anti-STAT3 (αSTAT3) antibodies.
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Related In: Results  -  Collection

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Figure 2: DSS-induced colitis in IL-6−/− and IFN-γ−/− mice. (A) Time course of body weight loss. WT C57BL6 mice or IL-6−/− or IFN-γ−/− mice (n = 3 for each knockout mice) were treated with 2% DSS for indicated periods, and body weight was measured daily. Relative body weight (%) compared with that of day 0 is plotted with a standard error. Results were analyzed using the t test. A P value of <0.05 was considered to be statistically significant. (B) Histological section of an ulcer with hematoxylin and eosin staining. Pathology was graded on a scale of 0–12. Data represent the average with SEM for the group. The average score for IL-6−/− mice, but not IFN-γ−/− mice, was significantly different from that for the WT mice (P = 0.013). Statistical analysis was performed using the t test. (C) STAT3 phosphorylation in the colon of WT and IL-6−/− mice treated with DSS. Colon tissue extracts from three independent mice of each strain were immunoblotted with anti–phospho-STAT3 (αPY-STAT3) and anti-STAT3 (αSTAT3) antibodies.
Mentions: STAT3 has been shown to be mainly activated by IL-6–related cytokines, and the elevation of the IL-6 level has been reported in DSS-induced colitis. On the other hand, IFN-γ has been shown to activate mainly STAT1. For this reason, we investigated the role of STAT3 in the pathology of DSS-induced colitis using IL-6−/− and IFN-γ−/− mice in a C57BL/6 background (Fig. 2). All IL-6+/+ mice developed severe colitis characterized by loss of weight, marked epithelial hyperplasia, extensive leukocyte infiltration, and goblet cell depletion. Inflammatory infiltrates, which consisted mainly of mononuclear cells, were observed in the lamina propria in WT mice. These changes were not very obvious in IL-6−/− mice (Fig. 2a and Fig. b). On the other hand, IFN-γ–deficient mice developed colitis as severely as WT mice. Then, we compared STAT3 activation in WT and IL-6−/− mice. As shown in Fig. 2 C, STAT3 phosphorylation in the colon of WT mice was much more intensive than that in IL-6−/− mice. These data suggest that STAT3 activation in intestinal cells contributes to the development of colitis and constitutive activation of STAT3 may prevent healing of colitis.

Bottom Line: We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation.Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis.These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Life Science, Kurume University, Kurume 839-0861, Japan.

ABSTRACT
Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell-dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

Show MeSH
Related in: MedlinePlus