RGD Reference Report - Control of inflammation by stromal Hedgehog pathway activation restrains colitis. - Rat Genome Database

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Control of inflammation by stromal Hedgehog pathway activation restrains colitis.

Authors: Lee, John J  Rothenberg, Michael E  Seeley, E Scott  Zimdahl, Bryan  Kawano, Sally  Lu, Wan-Jin  Shin, Kunyoo  Sakata-Kato, Tomoyo  Chen, James K  Diehn, Maximilian  Clarke, Michael F  Beachy, Philip A 
Citation: Lee JJ, etal., Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7545-E7553. doi: 10.1073/pnas.1616447113. Epub 2016 Nov 4.
RGD ID: 14975260
Pubmed: PMID:27815529   (View Abstract at PubMed)
PMCID: PMC5127312   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1616447113   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
IL10HumanExperimental Colitis treatmentISOIl10 (Mus musculus) RGD 
Il10RatExperimental Colitis treatmentISOIl10 (Mus musculus) RGD 
Il10MouseExperimental Colitis treatmentIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Il10  (interleukin 10)

Genes (Mus musculus)
Il10  (interleukin 10)

Genes (Homo sapiens)
IL10  (interleukin 10)


Additional Information