Effect of the Antimicrobial Peptide LL-37 on Gene Expression of Chemokines and 29 Toll-like Receptor-Associated Proteins in Human Gingival Fibroblasts Under Stimulation with Porphyromonas gingivalis Lipopolysaccharide.
Inomata. Megumi M; Horie. Toshi T; Into. Takeshi T
Key Findings
- LL‑37 is non‑toxic to human gum fibroblasts up to 10 µg/mL.
- When gum cells are exposed to Porphyromonas gingivalis LPS, LL‑37 reduces the LPS‑driven increase in inflammatory chemokines (IL‑8, CXCL10, CCL2).
- Without LPS, LL‑37 itself can raise IL‑8 and CCL2 levels, an effect that depends on the P2X7 receptor.
- LL‑37 lowers the expression of TLR4 and CD14 (key receptors for bacterial LPS) while raising negative regulators of TLR signaling (IRAK1, TNFAIP3, RNF216, TOLLIP, SIGIRR).
Practical Outcomes
- LL‑37 may be useful for modulating oral inflammation, but its dual pro‑ and anti‑inflammatory actions mean dosing and context matter a lot. For self‑experimenters, the safe concentration appears to be ≤10 µg/mL, yet the peptide’s effects on the P2X7 receptor suggest potential cytotoxicity at higher levels. More research is needed before recommending LL‑37 for routine health‑optimization protocols.
Summary
The study shows that the natural antimicrobial peptide LL‑37 can change how gum cells react to bacterial toxins. At low doses it isn’t toxic, but it can both boost and calm down inflammation depending on whether the cells are already exposed to bacterial LPS. It does this by acting on a receptor called P2X7 and by tweaking several immune‑related genes.
Abstract
The antimicrobial peptide LL-37 neutralizes the biological activity of lipopolysaccharide (LPS), while it upregulates the expression of several immune-related genes. We investigated the effect of LL-37 on gene regulation of human gingival fibroblasts (HGFs), stimulated with or without Porphyromonas gingivalis-derived LPS, a ligand for Toll-like receptor (TLR). LL-37 was non-toxic to HGFs up to a concentration of 10 μg/ml. P. gingivalis LPS upregulated the expression of IL8, CXCL10, and CCL2, whereas LL-37 reduced this upregulation. In absence of LPS, LL-37 itself upregulated the expression of IL8 and CCL2. LL-37 increased the expression of P2X7, which was constitutively expressed in HGFs. The P2X7 antagonist A-438079 suppressed the cytotoxicity and upregulatory effect of LL-37 on chemokine response, but not its downregulatory effect on P. gingivalis LPS-induced chemokine response. Whether LL-37 alters the expression of 29 genes that encode TLR-associated proteins, including TLRs, co-receptors, signaling molecules, and negative regulators, in HGFs, under stimulation with LPS, was examined. Among TLRs, P. gingivalis LPS upregulated the level of TLR4, whereas LL-37 reduced it. In co-receptors, LL-37 downregulated the level of CD14. Among signaling molecules, LL-37 augmented the LPS-upregulated expression of IRAK1. Similar effects were observed in the specific negative regulators TNFAIP3, RNF216, TOLLIP, and SIGIRR. Our results suggest that LL-37 exerts cytotoxicity and upregulation of chemokine response via the P2X7 receptor, while it induces downregulation of P. gingivalis LPS-induced chemokine response through alteration in the expression of 7 specific TLR-associated genes: downregulation of TLR4 and CD14 and upregulation of IRAK1, TNFAIP3, RNF216, TOLLIP, and SIGIRR.
Study Information
pubmed
2020
2019-11-04T00:00:00.000Z
10.1007/s12602-019-09600-2
16
47