Clinlcal-alimentary tractExpression of LL-37 by human gastric epithelial cells as a potential host defense mechanism against Helicobacter pylori☆
Section snippets
Antibodies, cytokines, and antimicrobial peptides
Preimmune chicken IgY, chicken IgY anti-LL-37 that recognizes the LL-37 peptide domain, and chicken IgY anti-hCAP18 antibody that recognizes the cathelin domain were as described earlier.39 Rabbit IgG anti-LL-37 antibody was a gift of B. Agerberth. Rabbit anti-H+, K+-ATPase (α-subunit) was from Calbiochem (San Diego, CA). Control rabbit serum and IgG were from Jackson ImmunoResearch Laboratories (West Grove, PA). Synthetic LL-37 peptide was from SynPep Corp. (Dublin, CA).40 Synthetic hBD-1 and
LL-37/hCAP18 mRNA and protein expression by normal human gastric epithelium
To determine if LL-37/hCAP18 was expressed by human gastric epithelium in vivo, mucosal biopsies of normal human antrum were analyzed for LL-37/hCAP18 mRNA expression by in situ hybridization. LL-37/hCAP18 mRNA was expressed by the luminal surface and adjacent gastric pit epithelium and by epithelium in the deeper gastric glands (Figure 1A and C). Similar results were obtained using gastric tissues from 3 additional individuals using probes directed to either the LL-37 or cathelin domains
Discussion
Gastric epithelial cells express LL-37/hCAP18 mRNA and protein and release this cathelicidin into gastric secretions. LL-37/hCAP18 was produced by those epithelial cells that line the luminal surface and upper gastric pits and by cells deeper in gastric glands but was absent from cells in the regenerative mucus neck zone. In addition, there was little, if any, LL-37/hCAP18 expression in regions of increased epithelial cell proliferation in hyperplastic polyps, by the surface epithelium in
Acknowledgements
We thank John Leopard and Jennifer Smith for technical assistance and Dr. Nissi Varki for pathological consultation.
References (67)
- et al.
Current status of defensins and their role in innate and adaptive immunity
FEMS Microbiol Lett
(2002) - et al.
Structural, functional analysis and localization of the human CAP18 gene
FEBS Lett
(1996) - et al.
Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid
Cell
(1996) - et al.
Urea hydrolysis in patients with Campylobacter pyloridis infection
Lancet
(1986) - et al.
Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells
Gastroenterology
(1997) - et al.
Induction of human beta-defensin-2 mRNA expression by Helicobacter pylori in human gastric cell line MKN45 cells on cag pathogenicity island
Biochem Biophys Res Commun
(1999) - et al.
Cathelicidin antimicrobial peptide expression in sweat, an innate defense system for the skin
J Invest Dermatol
(2002) - et al.
A standardized mouse model of Helicobacter pylori infectionintroducing the Sydney strain
Gastroenterology
(1997) - et al.
The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils
Blood
(1997) - et al.
Bacterial type IV secretionconjugation systems adapted to deliver effector molecules to host cells
Trends Microbiol
(2000)
Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37
J Biol Chem
The solution structures of the human beta-defensins lead to a better understanding of the potent bactericidal activity of HBD3 against Staphylococcus aureus
J Biol Chem
Epithelial peptide antibiotics
Biochem Pharmacol
Recent developments in the epidemiology of Helicobacter pylori
Gastroenterol Clin North Am
Helicobacter pylori Lewis expression is related to the host Lewis phenotype
Gastroenterology
How do bacteria resist human antimicrobial peptides?
Trends Microbiol
Regulation of human β-defensins by gastric epithelial cells in response to infection with Helicobacter pylori or stimulation with interleukin-1
Infect Immun
Expression of human beta-defensin 2 (hBD-2) in Helicobacter pylori induced gastritisantibacterial effect of hBD-2 against Helicobacter pylori
Gut
Lysozyme localization in normal and diseased human gastric and colonic mucosaA correlative histochemical, immunohistochemical and immunoelectron microscopic investigation
Apmis
Epithelial antimicrobial peptides in host defense against infection
Respir Res
Innate immunity and the normal microflora
Immunol Rev
Defensins and host defense
Science
Expression and regulation of the human β-defensins hBD-1 and hBD-2 in intestinal epithelium
J Immunol
Human beta-defensin-2 induction in Helicobacter pylori-infected gastric mucosal tissuesantimicrobial effect of overexpression
J Med Microbiol
Structural features and biological activities of the cathelicidin-derived antimicrobial peptides
Biopolymers
Cathelicidinsa family of endogenous antimicrobial peptides
Curr Opin Hematol
Cathelicidins, essential gene-encoded mammalian antibiotics
J Mol Med
Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium
Infect Immun
The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface
Proc Natl Acad Sci U S A
Bactericidal activity of mammalian cathelicidin-derived peptides
Infect Immunol
Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia
Infect Immun
Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils
Antimicrob Agents Chemother
Evaluation of the effects of peptide antibiotics human beta-defensins- 1/-2 and LL-37 on histamine release and prostaglandin D(2) production from mast cells
Eur J Immunol
Cited by (193)
Evolutionary diversification of defensins and cathelicidins in birds and primates
2023, Molecular ImmunologyHuman cathelicidin LL-37 exerts amelioration effects against EHEC O157:H7 infection regarding inflammation, enteric dysbacteriosis, and impairment of gut barrier function
2023, PeptidesCitation Excerpt :Our study confirmed the considerable infiltration of macrophages and neutrophils in O157 group. It has been reported that the infiltration of polymorphonuclear cells subsequently liberates reactive oxygen intermediates, proteolytic enzymes, and phospholipid derivatives, leading to further intestinal damage [28]. This suggests that not only EHEC colonization, but also the inflammatory response, may contribute to intestinal tissue damage.
Molecular modelling of the gastric barrier response, from infection to carcinogenesis
2021, Best Practice and Research: Clinical GastroenterologyHelicobacter pylori–Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense
2021, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :Next, in vivo gain-of-function experiments showed that Reg3b or β-defensin-1 administration significantly reduced H pylori colonization in gastric mucosa of WT mice (Figure 6E). As for the negative correlations between Rev-erbα and Reg3b/β-defensin-1 (Figure 6F) in gastric mucosa of H pylori–infected mice and host defense against H pylori from GEC-derived antibacterial proteins,17 we next found that, upon H pylori infection, GECs derived from Rev-erbα–/– mice produced more Reg3b and β-defensin-1 compared with those from WT mice (Figure 7A), and that supernatants from H pylori–infected GECs of Rev-erbα–/– mice exerted more pronounced killing activity against H pylori than those of WT mice (Figure 7B), which could be abrogated by blocking Reg3b or β-defensin-1 (Figure 7B). Finally, to explore the molecule mechanism of β-defensin-1 inhibition in GECs by Rev-erbα (human have no Reg3b gene), we performed luciferase reporter assays, and the results showed decreased activity of β-defensin-1-luc when transfected together with the Rev-erbα-pcDNA3.1, and retrieved activity when the Rev-erbα binding site on the β-defensin-1 promoter was mutated (Figure 7C); further ChIP assays showed that WT H pylori infection significantly increased binding activity to the β-defensin-1 promoter with the Rev-erbα antibodies (Abs) (Figure 7D), together suggesting that in WT H pylori–infected AGS cells, Rev-erbα directly inhibited β-defensin-1 expression.
- ☆
Supported by NIH grants DK58960 and DK35108 (to M.F.K.), DK53649 (to S.P.C.), AI052453 (to R.L.G.), and a VA Merit Award (to R.L.G.).