Abstract
Colonic brain-derived neurotrophic factor (BDNF) plays an essential role in pathogenesis of abdominal pain in diarrhea-predominant irritable bowel syndrome (IBS-D), but regulation on its expression remains unclear. We investigated the role of fecal supernatants (FSN) from IBS-D patients on regulating BDNF expression in colonic epithelial cells of human and mice. Using human Caco-2 cells, we found that IBS-D FSN significantly increased BDNF mRNA and protein levels compared to control FSN, which were remarkably suppressed by the serine protease inhibitor. To further explore the potential mechanisms, we investigated the impact of protease-activated receptor-2 (PAR-2) on BDNF expression. We found a significant increase in PAR-2 expression in Caco-2 after IBS-D FSN stimulation. Knockdown of PAR-2 significantly inhibited IBS-D FSN-induced upregulation of BDNF. Moreover, we found that phosphorylation of p38 MAPK, not NF-κB p65, contributed to PAR-2-mediated BDNF overexpression. To confirm these results, we intracolonically infused IBS-D or control FSN in mice and found that IBS-D FSN significantly elevated colonic BDNF and visceral hypersensitivity in mice, which were both suppressed by the inhibitor of serine protease or antagonist of PAR-2. Together, our data indicate that activation of PAR-2 signaling by IBS-D FSN promotes expression of colonic BDNF, thereby contributing to IBS-like visceral hypersensitivity.
Highlights
Hypersensitivity through a mechanism of protease activated receptor-2 (PAR-2) activation[8,9,10,11]
Enzyme-linked immunosorbent assay (ELISA) showed that brain-derived neurotrophic factor (BDNF) protein levels were 1.7-fold higher at 6 h and 2-fold higher at 24 h in culture supernatants from Irritable bowel syndrome (IBS)-D fecal supernatants (FSN)-treated cells than control FSN, with these effects prevented by FUT-175 either (Fig. 2b)
Immunohistochemistry staining showed that the increased BDNF in colon mainly localized in epithelial cells and lamina propria, leading us to speculate that this event likely originates from colonic epithelium[6]
Summary
Hypersensitivity through a mechanism of protease activated receptor-2 (PAR-2) activation[8,9,10,11]. PAR-2 action has been shown to be involved in secretory process of epithelial cells[12,13,14]. Along this line, whether the altered expression of intestinal epithelial BDNF in IBS-D patients can be attributed to the elevated fecal serine protease activity and subsequent activation of PAR-2 is worth further investigation. We conducted this study to examine the effect of colonic luminal fecal supernatants from IBS-D patients on expression of colonic epithelial BDNF, and the potential mechanism of how its release is regulated
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