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IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis

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IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis. / Jeffery, Victoria; Goldson, Andrew J; Dainty, Jack R; Chieppa, Marcello; Sobolewski, Anastasia.

In: Journal of Immunology, Vol. 199, No. 1, 01.07.2017, p. 304-311.

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@article{db99c7aff40544219f397b6b0d7c8cd9,
title = "IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis",
abstract = "Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells. Immunolabeling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking Ab to the IL-6 receptor or a neutralizing Ab to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP-positive stem cells per crypt compared with IgG-treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6-induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cells and the Wnt signaling pathway.",
author = "Victoria Jeffery and Goldson, {Andrew J} and Dainty, {Jack R} and Marcello Chieppa and Anastasia Sobolewski",
note = "Copyright {\textcopyright} 2017 by The American Association of Immunologists, Inc.",
year = "2017",
month = jul,
day = "1",
doi = "10.4049/jimmunol.1600960",
language = "English",
volume = "199",
pages = "304--311",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

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TY - JOUR

T1 - IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis

AU - Jeffery, Victoria

AU - Goldson, Andrew J

AU - Dainty, Jack R

AU - Chieppa, Marcello

AU - Sobolewski, Anastasia

N1 - Copyright © 2017 by The American Association of Immunologists, Inc.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells. Immunolabeling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking Ab to the IL-6 receptor or a neutralizing Ab to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP-positive stem cells per crypt compared with IgG-treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6-induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cells and the Wnt signaling pathway.

AB - Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells. Immunolabeling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking Ab to the IL-6 receptor or a neutralizing Ab to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP-positive stem cells per crypt compared with IgG-treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6-induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cells and the Wnt signaling pathway.

U2 - 10.4049/jimmunol.1600960

DO - 10.4049/jimmunol.1600960

M3 - Article

C2 - 28550196

VL - 199

SP - 304

EP - 311

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -

ID: 114915491