Precursor processing of human defensin-5 is essential to the multiple functions in vitro and in vivo

Abstract

Human defensin-5 (HD-5) is one of the major antimicrobial peptides secreted by Paneth cells in the human small intestine. HD-5 is produced and stored as a propeptide in Paneth cell granules, secreted in response to stimulation by cholinergic reagents or bacterial antigens. The activation process by trypsin occurs in the intestinal lumen to produce mature HD-5. This study evaluated the difference between proHD-5 and mature HD-5 in bactericidal activity and induction of chemokine secretion in vitro. Mature HD-5 showed bactericidal activities against all bacterial strains. Though, proHD-5 without enzymatic cleavage possessed less antimicrobial ability against Salmonella typhimurium and Escherichia coli but not against Staphylococcus aureus. Mature HD-5 also induced intestinal epithelial cells to increase the protein and mRNA levels of interleukin-8. Furthermore, the peptides were applied to dextran sulfate sodium-induced mouse colitis. The expression of endogenous mouse defensins was not changed in the small intestine, and the additional injection of exogenous HD-5 improved mortality (p < 0.05). This study demonstrated the multifunctional roles of the activation process in human defensin and the possibility of using antimicrobial peptides for the treatment of inflammatory bowel diseases in future applications.