Activation of epithelial STAT3 regulates intestinal homeostasis

Neufert, Clemens; Pickert, Geethanjali; Zheng, Yan; Wittkopf, Nadine; Warntjen, Moritz; Nikolaev, Alexei; Ouyang, Wenjun; Neurath, Markus F.; Becker, Christoph

doi:10.4161/cc.9.4.10615

Cited by 88 publications

(72 citation statements)

References 20 publications

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“…5). Consistent with the pivotal function of STAT3 in maintaining or restoring the IEC integrity in homeostasis or colitis (35,51), we furthermore found a severe proliferation defect in Tyk2 2/2 colonic epithelial cells (Fig. 6).…”

Section: Discussionsupporting

confidence: 61%

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Hainzl

Stockinger

Rauch

et al. 2015

The Journal of Immunology

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In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2−/− mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22–STAT3 target genes is reduced in IECs from healthy and colitic Tyk2−/− mice. Experiments with conditional Tyk2−/− mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22–Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22–dependent colitis was confirmed in Citrobacter rodentium–induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.

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Section: Discussionsupporting

confidence: 61%

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Hainzl

Stockinger

Rauch

et al. 2015

The Journal of Immunology

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“…We and others have previously shown that IL-22 signaling induces STAT3 activation in IECs upon mucosal damage, thereby promoting restoration of intestinal homeostasis (9,47,48). Strong STAT3 activation in IECs is also found upon infection with C. rodentium (49).…”

Section: Discussionmentioning

confidence: 90%

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

Backert

Koralov

Wirtz

et al. 2014

The Journal of Immunology

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The Citrobacter rodentium model mimics the pathogenesis of infectious colitis and requires sequential contributions from different immune cell populations, including innate lymphoid cells (ILCs) and CD4+ lymphocytes. In this study, we addressed the role of STAT3 activation in CD4+ cells during host defense in mice against C. rodentium. In mice with defective STAT3 in CD4+ cells (Stat3ΔCD4), the course of infection was unchanged during the innate lymphoid cell–dependent early phase, but significantly altered during the lymphocyte-dependent later phase. Stat3ΔCD4 mice exhibited intestinal epithelial barrier defects, including downregulation of antimicrobial peptides, increased systemic distribution of bacteria, and prolonged reduction in the overall burden of C. rodentium infection. Immunomonitoring of lamina propria cells revealed loss of virtually all IL-22–producing CD4+ lymphocytes, suggesting that STAT3 activation was required for IL-22 production not only in Th17 cells, but also in Th22 cells. Notably, the defective host defense against C. rodentium in Stat3∆CD4 mice could be fully restored by specific overexpression of IL-22 through a minicircle vector–based technology. Moreover, expression of a constitutive active STAT3 in CD4+ cells shaped strong intestinal epithelial barrier function in vitro and in vivo through IL-22, and it promoted protection from enteropathogenic bacteria. Thus, our work indicates a critical role of STAT3 activation in Th17 and Th22 cells for control of the IL-22–mediated host defense, and strategies expanding STAT3-activated CD4+ lymphocytes may be considered as future therapeutic options for improving intestinal barrier function in infectious colitis.

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“…In many tumor cells, CDK-cyclin complex are expressed aberrantly at high levels and thus make the normal control at G 1 /S or G 2 -M transition point ineffective (43,44). Recently, it has been shown that JSI-124 induced cell-cycle arrest in primary astrocytes and neural stem cells, mouse glioma cells, and human malignant peripheral nerve sheath tumor cells through inhibition of serine 727 phosphorylation of STAT3 (45,46).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Constitutive Activation of STAT3 by Curcurbitacin-I (JSI-124) Sensitized Human B-Leukemia Cells to Apoptosis

Ishdorj

Johnston

Gibson

2010

Molecular Cancer Therapeutics

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Phosphorylation of STAT3 on serine 727 regulates gene expression and is found to be elevated in many Bleukemia cells including chronic lymphocytic leukemia (CLL). It is, however, unclear whether targeting STAT3 will be an effective antileukemia therapy. In this study, we assessed in vitro antileukemia activity of the STAT3 inhibitor JSI-124 (cucurbitacin I). JSI-124 potently induces apoptosis in 3 B-leukemia cell lines (BJAB, I-83, and NALM-6) and in primary CLL cells and was associated with a reduction in serine 727 phosphorylation of STAT3. Similarly, knockdown of STAT3 expression induced apoptosis in these leukemia cells. In addition, we found that JSI-124 and knockdown of STAT3 decreased antiapoptotic protein XIAP expression and overexpression of XIAP blocked JSI-124-induced apoptosis. Furthermore, we found that combined treatment of JSI-124 and TRAIL increased apoptosis associated with an increase in death receptor 4 expression. Besides apoptosis, we found that JSI-124 also induced cell-cycle arrest prior to apoptosis in B-leukemia cells. This corresponded with reduced expression of the cell-cycle regulatory gene, cdc-2. Thus, we present here for the first time that JSI-124 induced suppression of serine 727 phosphorylation of STAT3, leading to apoptosis and cell-cycle arrest through alterations in gene transcription in B-leukemia cells.

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Activation of epithelial STAT3 regulates intestinal homeostasis

Cited by 88 publications

References 20 publications

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

Inhibition of Constitutive Activation of STAT3 by Curcurbitacin-I (JSI-124) Sensitized Human B-Leukemia Cells to Apoptosis

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