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Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7545-E7553. Epub 2016 Nov 4.

Control of inflammation by stromal Hedgehog pathway activation restrains colitis.

Lee JJ1,2,3,4, Rothenberg ME1,5, Seeley ES6, Zimdahl B1,2,3, Kawano S1,2,3, Lu WJ1,2,3, Shin K1,2,3,7, Sakata-Kato T8, Chen JK8, Diehn M1,9,10, Clarke MF1,4,10, Beachy PA11,2,3,10.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
2
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
3
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305.
4
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305.
5
Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305.
6
Department of Pathology, University of California, San Francisco, CA 94143.
7
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyumgbuk 37673, South Korea.
8
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305.
9
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305.
10
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305.
11
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; pbeachy@stanford.edu.

Abstract

Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4+Foxp3+ regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.

KEYWORDS:

Hedgehog signaling; colitis; colon cancer; inflammatory bowel disease; interleukin-10

PMID:
27815529
PMCID:
PMC5127312
DOI:
10.1073/pnas.1616447113
[Indexed for MEDLINE]
Free PMC Article

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