title: Increased production of BDNF in colonic epithelial cells induced by fecal supernatants from diarrheic IBS patients.
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.
authors.affiliation: 1] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China [2] Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: 1] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China [2] Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Fei-Xue
authors.initials: FX
authors.lastname: Chen
authors.affiliation: 1] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China [2] Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Du
authors.affiliation: 1] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China [2] Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Li
authors.affiliation: 1] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China [2] Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Yu
authors.affiliation: 1] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China [2] Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Zuo
authors.affiliation: 1] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China [2] Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Li
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D003106:Colon / Q000378:metabolism*; D004576:Electromyography; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000201:enzymology*; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism / Q000473:pathology; D043183:Irritable Bowel Syndrome / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044464:Receptor, PAR-2; C579455:BDNF protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D057057:Serine Proteases