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Natural molecules induce and synergize to boost expression of the human antimicrobial peptide ?-defensin-3.

ABSTRACT: Antimicrobial peptides (AMPs) are mucosal defense effectors of the human innate immune response. In the intestine, AMPs are produced and secreted by epithelial cells to protect the host against pathogens and to support homeostasis with commensals. The inducible nature of AMPs suggests that potent inducers could be used to increase their endogenous expression for the prevention or treatment of diseases. Here we aimed at identifying molecules from the natural pharmacopoeia that induce expression of human ?-defensin-3 (HBD3), one of the most efficient AMPs, without modifying the production of proinflammatory cytokines. By screening, we identified three molecules isolated from medicinal plants, andrographolide, oridonin, and isoliquiritigenin, which induced HBD3 production in human colonic epithelial cells. This effect was observed without activation of the NF-?B pathway or the expression of associated proinflammatory cytokines. We identified the EGF receptor as the target of these compounds and characterized the downstream-activated MAPK pathways. At the chromatin level, molecules increased phosphorylation of histone H3 on serine S10 and recruitment of the c-Fos, c-Jun, and Elk1 or c-Myc transcription factors at the HBD3 promoter. Interestingly, stimulating cells with a combination of andrographolide and isoliquiritigenin synergistically enhanced HBD3 induction 10-fold more than observed with each molecule alone. Finally, we investigated the molecular basis governing the synergistic effect, confirmed our findings in human colonic primary cells, and demonstrated that synergism increased cellular antimicrobial activity. This work shows the capability of small molecules to achieve induction of epithelial antimicrobial defenses while simultaneously avoiding the deleterious risks of an inflammatory response.

SUBMITTER: Sechet E

PROVIDER: S-EPMC6196494 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Natural molecules induce and synergize to boost expression of the human antimicrobial peptide β-defensin-3.

Sechet Emmanuel E Telford Erica E Bonamy Clément C Sansonetti Philippe J PJ Sperandio Brice B

Proceedings of the National Academy of Sciences of the United States of America 20181001 42

Antimicrobial peptides (AMPs) are mucosal defense effectors of the human innate immune response. In the intestine, AMPs are produced and secreted by epithelial cells to protect the host against pathogens and to support homeostasis with commensals. The inducible nature of AMPs suggests that potent inducers could be used to increase their endogenous expression for the prevention or treatment of diseases. Here we aimed at identifying molecules from the natural pharmacopoeia that induce expression o ...[more]

PMID: 30275324

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Project description:Human defensin 5 (HD5) is a 32-residue host-defense peptide expressed in the gastrointestinal, reproductive, and urinary tracts that has antimicrobial activity. It exhibits six cysteine residues that are regiospecifically oxidized to form three disulfide bonds (Cys(3)-Cys(31), Cys(5)-Cys(20), and Cys(10)-Cys(30)) in the oxidized form (HD5(ox)). To probe the solution structure and oligomerization properties of HD5(ox), and select mutant peptides lacking one or more disulfide bonds, NMR solution studies and analytical ultracentrifugation experiments are reported in addition to in vitro peptide stability assays. The NMR solution structure of HD5(ox), solved at pH 4.0 in 90:10 H(2)O/D(2)O, is presented (PDB: 2LXZ ). Relaxation T(1)/T(2) measurements and the rotational correlation time (τ(c)) estimated from a (15)N-TRACT experiment demonstrate that HD5(ox) is dimeric under these experimental conditions. Exchange broadening of the Hα signals in the NMR spectra suggests that residues 19-21 (Val(19)-Cys(20)-Glu(21)) contribute to the dimer interface in solution. Exchange broadening is also observed for residues 7-14 comprising the loop. Sedimentation velocity and equilibrium studies conducted in buffered aqueous solution reveal that the oligomerization state of HD5(ox) is pH-dependent. Sedimentation coefficients of ca. 1.8 S and a molecular weight of 14 363 Da were determined for HD5(ox) at pH 7.0, supporting a tetrameric form ([HD5(ox)] ≥ 30 μM). At pH 2.0, a sedimentation coefficient of ca. 1.0 S and a molecular weight of 7079 Da, corresponding to a HD5(ox) dimer, were obtained. Millimolar concentrations of NaCl, CaCl(2), and MgCl(2) have a negligible effect on the HD5(ox) sedimentation coefficients in buffered aqueous solution at neutral pH. Removal of a single disulfide bond results in a loss of peptide fold and quaternary structure. These biophysical investigations highlight the dynamic and environmentally sensitive behavior of HD5(ox) in solution, and provide important insights into HD5(ox) structure/activity relationships and the requirements for antimicrobial action.

Dataset Information

Natural molecules induce and synergize to boost expression of the human antimicrobial peptide ?-defensin-3.

Publications

Natural molecules induce and synergize to boost expression of the human antimicrobial peptide β-defensin-3.

Similar Datasets

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