Control of inflammation by stromal Hedgehog pathway activation restrains colitis.
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.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305.|Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305.
John J
JJ
Lee
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305.
Michael E
ME
Rothenberg
Department of Pathology, University of California, San Francisco, CA 94143.
E Scott
ES
Seeley
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305.
Bryan
B
Zimdahl
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305.
Sally
S
Kawano
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305.
Wan-Jin
WJ
Lu
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305.|Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyumgbuk 37673, South Korea.
Kunyoo
K
Shin
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305.
Tomoyo
T
Sakata-Kato
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305.
James K
JK
Chen
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305.
Maximilian
M
Diehn
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.|Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305.
Michael F
MF
Clarke
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; pbeachy@stanford.edu.|Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.|Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305.
Philip A
PA
Beachy
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D016264:Dextran Sulfate / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053823:Hedgehog Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C556062:IL10 protein, mouse; D054852:Small Molecule Libraries; D000071676:Zinc Finger Protein GLI1; D016753:Interleukin-10; D016264:Dextran Sulfate
Hedgehog signaling; colitis; colon cancer; inflammatory bowel disease; interleukin-10