title: Activation of epidermal growth factor receptor mediates mucin production stimulated by p40, a Lactobacillus rhamnosus GG-derived protein.
abstract: The mucus layer coating the gastrointestinal tract serves as the first line of intestinal defense against infection and injury. Probiotics promote mucin production by goblet cells in the intestine. p40, a Lactobacillus rhamnosus GG-derived soluble protein, has been shown to transactivate the EGF receptor (EGFR) in intestinal epithelial cells, which is required for inhibition of apoptosis and preservation of barrier function in the colon, thereby ameliorating intestinal injury and colitis. Because activation of EGFR has been shown to up-regulate mucin production in goblet cells, the purpose of this study was to investigate the effects and mechanisms of p40 regulation of mucin production. p40 activated EGFR and its downstream target, Akt, in a concentration-dependent manner in LS174T cells. p40 stimulated Muc2 gene expression and mucin production in LS174T cells, which were abolished by inhibition of EGFR kinase activity, down-regulation of EGFR expression by EGFR siRNA transfection, or suppression of Akt activation. Treatment with p40 increased mucin production in the colonic epithelium, thus thickening the mucus layer in the colon of wild type, but not of Egfr(wa5) mice, which have a dominant negative mutation in the EGFR kinase domain. Furthermore, inhibition of mucin-type O-linked glycosylation suppressed the effect of p40 on increasing mucin production and protecting intestinal epithelial cells from TNF-induced apoptosis in colon organ culture. Thus, these results suggest that p40-stimulated activation of EGFR mediates up-regulation of mucin production, which may contribute to the mechanisms by which p40 protects the intestinal epithelium from injury.
authors.affiliation: From the Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Lihong
authors.initials: L
authors.lastname: Wang
authors.affiliation: the Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, China, and.
authors.forename: Hailong
authors.initials: H
authors.lastname: Cao
authors.affiliation: From the Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.affiliation: the Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, China, and.
authors.forename: Bangmao
authors.initials: B
authors.lastname: Wang
authors.affiliation: the Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Harvard University Medical School, Boston, Massachusetts 02114.
authors.forename: W Allan
authors.initials: WA
authors.lastname: Walker
authors.affiliation: From the Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Sari A
authors.initials: SA
authors.lastname: Acra
authors.affiliation: From the Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee 37232, fang.yan@vanderbilt.edu.
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
mesh_terms: D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000494:pharmacology*; D002460:Cell Line; D003106:Colon / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D052201:Lacticaseibacillus rhamnosus / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055262:Mucin-2 / Q000235:genetics; D009077:Mucins / Q000096:biosynthesis*; D019936:Probiotics / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D001426:Bacterial Proteins; C524625:MUC2 protein, human; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D034741:RNA, Small Interfering; C560306:p40 protein, Lactobacillus rhamnosus; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: Apoptosis; Epidermal Growth Factor Receptor (EGFR); Goblet Cell; Intestine; Lactobacillus rhamnosus GG; Mucin; Mucus; Probiotic; Probiotics