MUC2 Mucin Regulates Cathelicidin in the Colon under Normal and Disease Conditions

Embedded in the colonic mucus layers are cathelicidins, small cationic peptides secreted by neutrophils and colonic epithelial cells.  Humans and mice have only one cathelin-related antimicrobial peptide (CRAMP), LL-37/hCAP-18 and Cramp respectively, with related structure and antimicrobial and chemotactic functions.  Altered production of MUC2 mucin and antimicrobial peptides is characteristic of colonic inflammation and disease.  However, the interactions between MUC2 mucin and cathelicidins in conferring innate immunity are not well characterized.  In this study, we quantified whether MUC-2 expression and release can regulate the expression and secretion of cathelicidin LL-37 in human colonic goblet cells. Even though LL-37 was released at basal levels it was enhanced when goblet cells were stimulated with sodium butyrate (a normal product of colonic bacterial fermentation) or IL-1β (hallmark pro-inflammatory cytokine in colitis). Activation of cyclic adenylyl cyclase (AMP) and mitogen-activated protein-kinase (MAPK) signaling pathways, but not phosphatidylinositol 3-kinase, was necessary for the simultaneous expression of MUC2 and cathelicidins. In animals, Muc2 production regulated cathelicidin evidence by markedly reduced Cramp in Muc2^-/- as compared to Wt Muc2^+/+ littermates.  A similar response was noted in DSS-induced colitis with a reduced mucus barrier and in closed colonic loops inoculated with the colonic parasite Entamoeba histolytica.  These studies show a regulatory mechanism between MUC-2 and cathelicidins in the colonic mucosa where an intact mucus barrier is essential for expression and secretion of cathelicidins.  Defects in MUC2 mucin, hallmarks in IBDs, may impair cathelicidin response and influence the outcome of abiotic and infectious colitis.