THERAPEUTIC EFFECT OF ORIDONIN AGAINST INFLAMMATORY BOWEL DISEASE INVOLVES INHIBITION OF INTESTINAL FIBROSIS VIA NF-?B AND P38/STAT1 PATHWAYS
Rui-Min D. Mao*, Xiaofu Wang, Yanping Gu, Ravi Radhakrishnan
The University of Texas Medical Branch at Galveston, Galveston, TX
Introduction
Intestinal fibrosis is a common sequela of inflammatory bowel disease (IBD) that may result in serious complications such as stricture and obstruction. In response to inflammatory stimuli, intestinal epithelial cells may undergo epithelial-mesenchymal transition (EMT), a process in which epithelial cells acquire a mesenchymal-like phenotype and participate in IBD-related fibrosis. Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to have therapeutic effects on IBD. However, the cellular mechanism remains unclear. We hypothesized that oridonin attenuates inflammation-related EMT and fibrogenesis in intestinal epithelial cells.
Methods
The rat intestinal epithelial cell line IEC-6 was exposed to lipopolysaccharide (LPS) after pretreatment with or without oridonin. Cellular protein levels were analyzed with Western blot or immunofluorescence assay.
Results
Oridonin treatment suppressed LPS-induced activation of ?-smooth muscle actin (?-SMA), a marker of myofibroblasts, in IEC-6 cells. NF-?B was found to be an important regulator of ?-SMA. Oridonin inhibited LPS-induced NF-?B activation by blocking TNF?-induced NF-?B p65 nuclear translocation and DNA binding activity. TNF?-induced phosphorylation of IKK?/?, I?B?, and total I?B? degradation were inhibited by oridonin. Meanwhile, LPS-induced ?-SMA activation was found to be attenuated by the p38 specific inhibitor SB352085 but not by MEK/ERK or JNK inhibitors. Interestingly, oridonin did not affect LPS-stimulated p38 phosphorylation but significantly inhibited Stat1 activity, a downstream factor of p38. In addition, oridonin prevented LPS-stimulated fibronectin expression and restored LPS-inhibited tight junction protein ZO-1 expression in IEC-6 cells.
Conclusion
The anti-inflammatory effects of oridonin on intestinal epithelial cells may function by suppressing LPS-induced NF-?B and p38/Stat1 pathways and EMT-related fibrogenesis. Oridonin may be a promising drug candidate for IBD.
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