TNFα-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFκB signaling

Author:

Amasheh Maren1,Fromm Anja12,Krug Susanne M.2,Amasheh Salah2,Andres Susanne1,Zeitz Martin1,Fromm Michael2,Schulzke Jörg-Dieter13

Affiliation:

1. Department of Gastroenterology, Charité, Campus Benjamin Franklin, Berlin 12200, Germany

2. Institute of Clinical Physiology, Charité, Campus Benjamin Franklin, Berlin 12200, Germany

3. Department of General Medicine, Charité, Campus Benjamin Franklin, Berlin 12200, Germany

Abstract

TNFα-mediated tight junction defects contribute to diarrhea in inflammatory bowel diseases (IBDs). In our study, the signaling pathways of the TNFα effect on barrier- or pore-forming claudins were analyzed in HT-29/B6 human colon monolayers. Berberine, a herbal therapeutic agent that has been recently established as a therapy for diabetes and hypercholesterinemia, was able to completely antagonize the TNFα-mediated barrier defects in the cell model and in rat colon. Ussing chamber experiments and two-path impedance spectroscopy revealed a decrease of paracellular resistance after TNFα to 11±4%, whereas transcellular resistance was unchanged. The permeability of the paracellular marker fluorescein was increased fourfold. Berberine alone had no effect while it fully prevented the TNFα-induced barrier defects. This effect on resistance was confirmed in rat colon. TNFα removed claudin-1 from the tight junction and increased claudin-2 expression. Berberine prevented TNFα-induced claudin-1 disassembly and upregulation of claudin-2. The effects of berberine were mimicked by genistein plus BAY11-7082, indicating that they are mediated via tyrosine kinase, pAkt and NFκB pathways. In conclusion, the anti-diarrheal effect of berberine is explained by a novel mechanism, suggesting a therapeutic approach against barrier breakdown in intestinal inflammation.

Publisher

The Company of Biologists

Subject

Cell Biology

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