title: MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis.
abstract: Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP) each, LL-37/hCAP-18 and Cramp, respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity againstEntamoeba histolyticaare not well characterized. In this study, we quantified whether MUC2 expression and release could regulate the expression and secretion of cathelicidin LL-37 in colonic epithelial cells and in the colon. The synthesis of LL-37 was enhanced with butyrate (a product of bacterial fermentation) and interleukin-1β (IL-1β) (a proinflammatory cytokine in colitis) in the presence of exogenously added purified MUC2. The LL-37 responses to butyrate and IL-1β were higher in high-MUC2-producing cells than in lentivirus short hairpin RNA (shRNA) MUC2-silenced cells. Activation of cyclic adenylyl cyclase (AMP) and mitogen-activated protein kinase (MAPK) signaling pathways was necessary for the simultaneous expression of MUC2 and cathelicidins. In Muc2 mucin-deficient (Muc2-/-) mice, murine cathelicidin (Cramp) was significantly reduced compared to that inMuc2+/-andMuc2+/+littermates.E. histolytica-induced acute inflammation in colonic loops stimulated high levels of cathelicidin inMuc2+/+but not inMuc2-/-littermates. In dextran sodium sulfate (DSS)-induced colitis inMuc2+/+mice, which depletes the mucus barrier and goblet cell mucin,Crampexpression was significantly enhanced during restitution. These studies demonstrate regulatory mechanisms between MUC2 and cathelicidins in the colonic mucosa where an intact mucus barrier is essential for expression and secretion of cathelicidins in response toE. histolytica-and DSS-induced colitis.
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Cobo
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kissoon-Singh
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: France
authors.initials: F
authors.lastname: Moreau
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Ravi
authors.initials: R
authors.lastname: Holani
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada kchadee@ucalgary.ca.
authors.forename: Kris
authors.initials: K
authors.lastname: Chadee
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D002087:Butyrates / Q000378:metabolism*; D002460:Cell Line; D003092:Colitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004748:Entamoeba histolytica; D004749:Entamoebiasis / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D013431:Sulfates / Q000009:adverse effects; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D002087:Butyrates; D055262:Mucin-2; D012333:RNA, Messenger; D013431:Sulfates; C012036:sodium sulfate; D020928:Mitogen-Activated Protein Kinases; D054804:Cathelicidins
keywords: Entamoeba histolytica; MUC2; antimicrobial peptides; mucin