Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease

Coskun, Mehmet; Salem, Mohammad; Pedersen, Jannie; Nielsen, Ole Haagen

doi:10.1016/j.phrs.2013.06.007

Cited by 272 publications

(191 citation statements)

References 145 publications

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“…Together, these data suggest that the barrier function of colonic epithelium is impaired in HU mice. As some pathways or cytokines, including type I IFN pathway and IL-18, are involved in regulating epithelial cell turnover under steady-state condition (44,45), these alterations may further deteriorate mucosal homeostasis.…”

Section: Reduced Defense Response In the Colon Epithelium Of Hu Micementioning

confidence: 99%

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

Shi

Wang

et al. 2017

FASEB j.

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Exposure to microgravity leads to alterations in multiple systems, but microgravity-related changes in the gastrointestinal tract and its clinical significance have not been well studied. We used the hindlimb unloading (HU) mouse model to simulate a microgravity condition and investigated the changes in intestinal microbiota and colonic epithelial cells. Compared with ground-based controls (Ctrls), HU affected fecal microbiota composition with a profile that was characterized by the expansion of Firmicutes and decrease of Bacteroidetes. The colon epithelium of HU mice showed decreased goblet cell numbers, reduced epithelial cell turnover, and decreased expression of genes that are involved in defense and inflammatory responses. As a result, increased susceptibility to dextran sulfate sodium-induced epithelial injury was observed in HU mice. Cohousing of Ctrl mice with HU mice resulted in HUlike epithelial changes in Ctrl mice. Transplantation of feces from Ctrl to HU mice alleviated these epithelial changes in HU mice. Results indicate that HU changes intestinal microbiota, which leads to altered colonic epithelial cell homeostasis, impaired barrier function, and increased susceptibility to colitis. We further demonstrate that alteration in gastrointestinal motility may contribute to HU-associated dysbiosis. These animal results emphasize the necessity of evaluating astronauts' intestinal homeostasis during distant space travel.-Shi, J., Wang, Y., He, J., Li, P., Jin, R., Wang, K., Xu, X., Hao, J., Zhang, Y., Liu, H., Chen, X., Wu, H., Ge, Q. Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model. FASEB J. 31, 3695-3709 (2017 Exposure to microgravity leads to alterations, such as bone demineralization, muscle atrophy, cardiovascular deconditioning, and immune dysfunction, in multiple systems (1). Limited reports also suggest that spaceflight and microgravity affect the integrity of intestinal epithelium. For instance, reduced length of villi and depth of crypts was found in rats that were flown on 12-d Cosmos 2044 and Foton M3 missions (2, 3), and decreased mucin production of intestinal epithelial cells was shown in rats that were flown on the 19.5-d Cosmos 605 mission (4). Colonic TGF-b expression was altered in mice aboard the 13-d STS-135 or 91-d International Space Station missions (5, 6). Using a well-accepted, ground-based spaceflight analog, the hindlimb unloading (HU) mouse model (7) found that simulated microgravity resulted in a transient increase in intestinal permeability, which is characterized by the elevation of circulating LPS and the activation of the innate immune system. The clinical significance and mechanism of these epithelial changes are not clear; however, Chopra et al. (8) reported that HU mice that were infected with Salmonella enterica serovar typhimurium had a 100-fold decrease in LD 50 compared with normal-gravity control (Ctrl) mice. This indicates that microgravity-induced intestinal epithelial changes may exacerbate bacte...

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Section: Reduced Defense Response In the Colon Epithelium Of Hu Micementioning

confidence: 99%

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

Shi

Wang

et al. 2017

FASEB j.

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“…In a screen for susceptibility factors in inflammatory bowel disease (IBD), polymorphisms in the Tyk2 and Stat3 loci were found (9). We recently identified that IFN-I and IFN-III signals are involved in the progression and resolution of colitis (10,11).…”

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confidence: 99%

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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“…Белки класса Янус-киназ (JAK) являют-ся внутриклеточными мессенджерами, обеспечивающими процесс сигнальной трансдукции [41,42]. JAK экспрессиру-ются в иммунокомпетентных клетках, включая гранулоциты и лимфоциты, и играют важнейшее значение в сиг-нальных путях IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, IL-21, интерферона-γ и других цитокинов [42,43].…”

Section: инфликсимабunclassified

Targeted therapy of inflammatory bowel diseases: realities and prospects

Маев¹,

Андреев²

2018

Med. sov.

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Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease

Cited by 272 publications

References 145 publications

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

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

Targeted therapy of inflammatory bowel diseases: realities and prospects

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