MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis

• Published in: Infection and immunity Vol. 85; no. 3
• Main Authors: Cobo, Eduardo R, Kissoon-Singh, Vanessa, Moreau, France, Holani, Ravi, Chadee, Kris
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-03-2017
• Subjects: Animals; Antimicrobial Cationic Peptides - biosynthesis; Antimicrobial Cationic Peptides - genetics; Butyrates - metabolism; Cell Line; Colitis - etiology; Colitis - metabolism; Colitis - pathology; Disease Models, Animal; Entamoeba histolytica; Entamoebiasis - metabolism; Entamoebiasis - parasitology; Entamoebiasis - pathology; Fungal and Parasitic Infections; Gene Expression; Humans; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - parasitology; Intestinal Mucosa - pathology; Male; MAP Kinase Signaling System; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases - metabolism; Mucin-2 - genetics; Mucin-2 - metabolism; RNA, Messenger - genetics; Sulfates - adverse effects; Entamoeba histolytica; MUC2; mucin; antimicrobial peptides
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/iai.00905-16

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 against
are 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 (
) mice, murine cathelicidin (
) was significantly reduced compared to that in
and
littermates.
-induced acute inflammation in colonic loops stimulated high levels of cathelicidin in
but not in
littermates. In dextran sodium sulfate (DSS)-induced colitis in
mice, which depletes the mucus barrier and goblet cell mucin,
expression 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 to
and DSS-induced colitis.