Potential Role of Epithelial Cell-Derived Histone H1 Proteins in Innate Antimicrobial Defense in the Human Gastrointestinal Tract

Abstract

In the human gastrointestinal tract, microorganisms are present in large numbers in the colon but are sparse in the proximal small intestine. In this study, we have shown that acid extracts of fresh human terminal ileal mucosal samples mediate antimicrobial activity. Following cation-exchange chromatography, one of the eluted fractions demonstrated antibacterial activity against bacteria normally resident in the human colonic lumen. This activity was further fractionated by reverse-phase high-performance liquid chromatography and identified as histone H1 and its fragments. We have also shown that in tissue sections, immunoreactive histone H1 is present in the cytoplasm of villus epithelial cells. In vitro culturing of detached (from the basement membrane) villus epithelial cells led to the release of antimicrobial histone H1 proteins, while the cells demonstrated ultrastructural features of programmed cell death. Our studies suggest that cytoplasmic histone H1 may provide protection against penetration by microorganisms into villus epithelial cells. Moreover, intestinal epithelial cells released into the lumen may mediate antimicrobial activity by releasing histone H1 proteins and their fragments.

Antimicrobial activities of heparin‐binding peptides

“…Hence, ongoing analyses in our laboratories involve studies of antimicrobial and laminin-containing heparin-binding peptide fractions derived from human basement membranes, as well as characterization of heparin-binding peptides generated by proteolytic cleavage of human complement factor C3 and other plasma proteins. [15] and the reported antibacterial protein human histone H1B [28] (upper). Homology is also found between another heparin-binding motif (TXXBXX TBXXXTBB) [12,14] and the known antibacterial peptide dermaseptin [29] from the two-coloured leaf frog 1 (lower).…”

Isolation and identification of antimicrobial components from the epidermal mucus of Atlantic cod (Gadus morhua)

“…Previous studies have suggested that histones have additional functions, including hormone activity [25], activation of leucocytes in salmon [26] and as part of the antimicrobial defence in mammals [27][28][29]. Even if the antimicrobial effect of histones has been known for decades [30], they were just recently linked to the innate immune system of frog [31], fish [2,3,15,16,[32][33][34][35][36] and mammals [29,37,38]. In the study by Robinette et al [15], a histone 2B-like protein was shown to inhibit important bacterial and fungal pathogens of fish, e.g.…”

“…These complexes have been named neutrophil extracellular traps and are highly bactericidal. By using immunohistochemical analysis, it was reported that histone H1 in human terminal ileal mucosa is not only localized to the nucleus but also in the cytoplasm [29]. Histones H2A and H2B were also shown to be present in the cytoplasm of syncytiotrophoblasts and amnion epithelial cells.…”

Antimicrobial effects of H4‐(86–100), histogranin and related compounds – possible involvement of DNA gyrase

“…Their inhibitory potencies in E. coli (LD 50 : 3.48 and 4.34 lgAEmL )1 ) are comparable to that of the antimicrobial peptide LL-37 (LD 50 : 4.10 lgAEmL )1 ). The antimicrobial activities of H4-(86-100) and HNr depend upon the integrity of the molecules, as precursors [H4-(84-102), pro-HNr] and fragments [bovine histogranin (HNb)-(1-13), HNb- (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), H4-(89-102) or OGP] are at least five times less potent than the parent peptides. Among various HN-like compounds, cyclo-(-Gly-pCl-Phe-Tyr-d-Arg) (compound 3) and N-5-guanidino pentanamide-(2R)-yl-2-N-(p-hydroxyphenylacetyl)-4-(p-chlorobenzoyl)-phenylene diamine (compound 8) display antimicrobial activities comparable to that of HNr.…”