Retinoic acid deficiency reprograms lamina propria dendritic cells to drive inflammation and tumor growth in spontaneous intestinal neoplasia
Abstract/Contents
- Abstract
- In the Adenomatous Polyposis Coli Multiple intestinal neoplasia (APCMin/+) mouse model of Familial Adenomatous Polyposis (FAP), T helper 17 (Th17) cells mediate tumor-promoting intestinal inflammation, but the underlying cause of inflammation is unknown. We find that in contrast to wild type lamina propria dendritic cells (LPDCs), which maintain intestinal tolerance by inducing TReg formation, APCMin/+ LPDCs instead induce Th17 formation. The reprogramming of LPDCs is due to a local deficit of the vitamin A metabolite, retinoic acid (RA), which results from insufficient synthesis and excessive breakdown of RA by gut associated Raldh and CYP enzymes, respectively. Exposure of APCMin/+ LPDCs to RA in vitro neutralizes their inflammatory phenotype. Treatment of mice with Liarozole, a CYP inhibitor, restores intestinal RA, eliminates Th17 inflammation and markedly reduces adenoma formation, whereas a vitamin A-deficient diet exacerbates disease. Elevated IL-17 and dysregulated vitamin A metabolism were also observed in FAP adenomas, suggesting that the same mechanism responsible for tumor-promoting intestinal inflammation in APCMin/+ mice applies to humans.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Leong, Hwei Xian |
|---|---|
| Associated with | Stanford University, Program in Immunology. |
| Primary advisor | Engleman, Edgar G |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Butcher, Eugene |
| Thesis advisor | Contag, Christopher H |
| Thesis advisor | Negrin, Robert S |
| Advisor | Butcher, Eugene |
| Advisor | Contag, Christopher H |
| Advisor | Negrin, Robert S |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Hwei Xian Leong. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis (Ph. D.)--Stanford University, 2012. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Hwei Xian Leong
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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