Journal
INFLAMMATORY BOWEL DISEASES
Volume 22, Issue 3, Pages 539-547Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MIB.0000000000000646
Keywords
tumor necrosis factor; epithelial sodium channel; sodium transport; lymphocytic colitis; MEK1/2
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [Schu 559/10-2, FOR 721/2]
- Volkswagenstiftung (Lichtenberg Program)
Ask authors/readers for more resources
Background: Lymphocytic colitis (LC) causes watery diarrhea. We aimed to identify mechanisms of altered Na+ absorption and regulatory inputs in patients with LC by examining the epithelial Na+ channel (ENaC) function as the predominant Na+ transport system in human distal colon. Methods: Epithelial Na+ channel function and regulation was analyzed in biopsies from sigmoid colon of patients with LC and in rat distal colon in Ussing chambers. ENaC-subunit expression was measured by real-time PCR and RNA sequencing. Correction factors for subepithelial resistance contributions were determined by impedance spectroscopy. Upstream regulators in LC were determined by RNA sequencing. Results: Epithelial Na+ channel-mediated electrogenic Na+ transport was inhibited despite aldosterone stimulation in human sigmoid colon of patients with LC. The increase in gamma-ENaC mRNA expression in response to aldosterone was MEK1/2-dependently reduced in LC, since it could be restored toward normal by MEK1/2 inhibition through U0126. Parallel experiments for identification of signaling in rat distal colon established MEK1/2 to be activated by a cytokine cocktail of TNF alpha, IFN gamma, and IL-15, which were identified as the most important regulators in the upstream regulator analysis in LC. Conclusions: In the sigmoid colon of patients with LC, the key effector cytokines TNF alpha, IFN gamma, and IL-15 inhibited gamma-ENaC upregulation in response to aldosterone through a MEK1/2-mediated pathway. This prevents ENaC to reach its maximum transport capacity and results in Na+ malabsorption which contributes to diarrhea.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available