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

• DOI: 10.1242/jcs.070896
• Publication Date: 2010-11-10T03:03:26Z
• Authors: Maren Amasheh; Anja Fromm; Susanne M. Krug; Salah Amasheh; Susanne Andres; Martin Zeitz; Michael Fromm; Jörg-Dieter Schulzke
• Keywords: Male; 0301 basic medicine; Berberine; Colon; Tumor Necrosis Factor-alpha; In Vitro Techniques; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Rats; Tight Junctions; 3. Good health; Oncogene Protein v-akt; 03 medical and health sciences; Cell Line, Tumor; NF-kappaB-Inducing Kinase; Animals; Humans; Rats, Wistar; Signal Transduction

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.