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Published on: April 21, 2015
Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB
Karen L Edelblum1, M Kay Washington, Tatsuki Koyama
1Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA.
Background & Aims:
Raf-1 kinase is a key regulator of a number of cellular processes, which promote the maintenance of a healthy colon epithelium. This study addresses the role of Raf in epithelial cell survival in response to dextran sulfate sodium (DSS)-induced injury and inflammation.
Methods:
Inducible intestinal epithelium-specific Raf knockout mice were generated and subjected to acute colitis followed by a short recovery period. Colon sections were analyzed by in situ oligo ligation or immunostaining for Ki67, phospho-extracellular signal regulated kinase, and nuclear factor-kappaB p65. Western blot analysis and terminal deoxynucleotidyl transferase nick-end labeling assays were performed on Raf small interfering RNA-transfected young adult mouse colon cells following DSS treatment.
Results:
We report that Raf protects against epithelial injury and inflammation and promotes recovery from acute DSS-induced colitis by both MAPK/ERK kinase (MEK)-dependent and -independent pathways. Furthermore, we demonstrate that Raf induces novel cell survival responses through activating nuclear factor-kappaB in a MEK-independent manner.
Conclusions:
These novel findings indicate a protective role for Raf in colon epithelium following ulcerative damage through inhibiting cell apoptosis and promoting proliferation with important implications for responses such as inflammation-associated carcinogenesis.
Insights
Raf kinase plays a protective role in colon epithelial cells, promoting survival and recovery from dextran sulfate sodium (DSS)-induced injury and inflammation. This involves both MEK-dependent and -independent pathways, including activating nuclear factor-kappaB.
Area of Science:
- Gastroenterology
- Molecular Biology
- Cell Biology
Background:
- Raf-1 kinase is crucial for maintaining colon epithelium health.
- Its role in epithelial cell survival during injury and inflammation requires further investigation.
Purpose of the Study:
- To investigate the function of Raf in colon epithelial cell survival following dextran sulfate sodium (DSS)-induced injury.
- To elucidate the mechanisms by which Raf influences recovery from colitis.
Main Methods:
- Generated inducible intestinal epithelium-specific Raf knockout mice.
- Analyzed colon sections using immunostaining and Western blot analysis.
- Utilized Raf small interfering RNA-transfected mouse colon cells.
Main Results:
- Raf protects against epithelial injury and inflammation in DSS-induced colitis.
- Raf promotes recovery through both MAPK/ERK kinase (MEK)-dependent and -independent pathways.
- Raf activates nuclear factor-kappaB in a MEK-independent manner, inducing cell survival responses.
Conclusions:
- Raf has a protective role in the colon epithelium after ulcerative damage.
- Raf inhibits apoptosis and promotes proliferation, impacting inflammation-associated carcinogenesis.
- These findings highlight Raf as a potential therapeutic target for colon injury and related diseases.
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