Paneth cell defensins: Endogenous peptide components of intestinal host defense

Abstract

Paneth cells are epithelial granulocytes at the base of the crypts of Lieberkühn in the small intestine of many mammalian species. These secretory cells contribute to mucosal barrier function by the apical release of granules containing a variety of antimicrobial products, including peptides termed cryptdins, for crypt defensins. In mice, six Paneth cell defensins have been characterized at the peptide level that have potent antimicrobial activities equivalent to or greater than that of rabbit neutrophil defensin NP-1. Cryptdin peptides that differ only by single amino acid substitutions have been shown to exhibit a high degree of specificity against certain target microorganisms. Cryptdins are coded by separate, two-exon genes that are located on chromosome 8 in both mice and humans. Human Paneth cells contain high levels of two different defensin mRNAs, but in mice at least 19 cryptdin isoforms are predicted from cDNA sequencing data. The mouse cryptdin-4 gene is expressed with positional specificity along the longitudinal intestinal axis, and cryptdin genes are active in the intestinal epithelium prior to Paneth cell differentiation. Accordingly, Paneth cell defensins are early markers of crypt ontogeny and are therefore useful in studies of lineage determination in the intestinal epithelium. Because cryptdins mediate innate immunity in the hostile environment of the intestinal lumen, it should be of interest to define biochemical and biophysical attributes that adapt these peptides to barrier function of mucosal surfaces.

Large-scale synthesis and functional elements for the antimicrobial activity of defensins

“…They are composed of 29-42 amino acids and contain three disulphide bonds, formed by three pairs of cysteine residues [1][2][3][4]. Defensins have been isolated from various tissue sources, such as mammalian trachea, intestine, tongue and skin, and human plasma, oral mucosa, salivary glands, saliva and ocular surface [5][6][7][8][9][10][11][12][13]. Defensins are involved in the oxygenindependent mechanism of the host immune response [14].…”

Pepsin-Mediated Processing of the Cytoplasmic Histone H2A to Strong Antimicrobial Peptide Buforin I

“…The expression of individual members of gene families that encode antimicrobial peptides is tissue specific. Antimicrobial peptides can function intracellularly, as in circulating leukocytes or in the external environment after release by secretory cells and other granulated epithelia (8). Certain antimicrobial peptides have diverse functions beyond microbicidal activity, such as promotion of wound healing (9) and chemotaxis of dendritic and memory T cells (10).…”

Cloning and Characterization of the Gene for a New Epithelial β-Defensin

“…Mammalian defensins constitute a large family of endogenous peptide antibiotics with broad spectrum activity against various bacteria, mycobacteria, fungi, and viruses (1)(2)(3)(4). Upon microbial invasion, mature active defensins are released quickly by proteolytic processing from precursor peptides either in cytoplasmic granules of most mammalian neutrophils and macrophages or in epithelial cells of the respiratory, gastroenteric, and urogenital tracts (2)(3)(4)(5).…”

“…Upon microbial invasion, mature active defensins are released quickly by proteolytic processing from precursor peptides either in cytoplasmic granules of most mammalian neutrophils and macrophages or in epithelial cells of the respiratory, gastroenteric, and urogenital tracts (2)(3)(4)(5). Killing of bacteria by defensins appears to involve direct interactions with target cell membranes, followed by insertion and permeabilization of membranes by forming multimeric pores (1-4, 6 -9).…”

“…Based on the positions of six cysteine residues and linkages of the disulfide bonds, defensins are divided further into two groups: ␣-and ␤-defensins. In contrast to most ␣-defensins, which are of myeloid origin and expressed constitutively in granulocytic leukocytes, many ␤-defensins are synthesized inducibly by epithelial cells during inflammation and infection (2)(3)(4)11). Interestingly, despite a lack of similarity in nucleotide and amino acid sequences between these two groups, all ␣-and ␤-defensin genes are clustered in close proximity on the same chromosome, as demonstrated in humans (12)(13)(14)(15), mice (16,17), cattle (18,19), and sheep (19,20).…”