Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages.
Zughaier. Susu M SM; Shafer. William M WM; Stephens. David S DS
Key Findings
- LL‑37 and similar peptides suppress endotoxin‑induced TNF‑alpha and nitric‑oxide release in human and mouse macrophages.
- Pre‑exposure to LL‑37 plus endotoxin dramatically increases ROS (respiratory burst) output compared to either alone.
- The ROS amplification occurs even in TLR4‑deficient cells, indicating a TLR4‑independent, likely direct effect on NADPH‑oxidase.
Practical Outcomes
- LL‑37 could be considered for strategies that aim to reduce inflammatory cytokine spikes, but users should be aware it may also raise oxidative stress. If you boost LL‑37 (e.g., via vitamin D or other means), pairing it with antioxidants might help balance the increased ROS. No specific dosing guidance is available yet, so treat this as a mechanistic insight rather than a ready‑to‑use protocol.
Summary
The study shows that the antimicrobial peptide LL‑37 can calm down inflammation caused by bacterial toxins by lowering TNF‑alpha and nitric‑oxide release, but at the same time it makes immune cells fire off more reactive oxygen species (ROS), a kind of oxidative burst. This boost in ROS happens even when the usual toxin‑sensing pathway (TLR4) is missing, meaning LL‑37 acts directly on the cell’s ROS‑producing machinery.
Abstract
Antimicrobial peptides (AMPs), in addition to their antibacterial properties, are also chemotactic and signalling molecules that connect the innate and adaptive immune responses. The role of AMP [alpha defensins, LL-37, a cathepsin G-derived peptide (CG117-136), protegrins (PG-1), polymyxin B (PMX) and LLP1] in modulating the respiratory burst response in human and murine macrophages in the presence of bacterial endotoxin [lipopolysaccharide (LPS) or lipooligosaccharide (LOS)] was investigated. AMP were found to neutralize endotoxin induction of nitric oxide and TNFalpha release in macrophages in a dose-dependent manner. In contrast, macrophages primed overnight with AMP and LOS or LPS significantly enhanced reactive oxygen species (ROS) release compared with cells primed with endotoxin or AMP alone, while no responses were seen in unprimed cells. This enhanced ROS release by macrophages was seen in all cell lines including those obtained from C3H/HeJ (TLR4-/-) mice. Similar effects were also seen when AMP and endotoxin were added directly with zymosan to trigger phagocytosis and the respiratory burst in unprimed RAW 264.7 and C3H/HeJ macrophages. Amplification of ROS release was also demonstrated in a cell-free system of xanthine and xanthine oxidase. Although AMP inhibited cytokine and nitric oxide induction by endotoxin in a TLR4-dependent manner, AMP and endotoxin amplified ROS release in a TLR4-independent manner possibly by exerting a prolonged catalytic effect on the ROS generating enzymes such as the NADPH-oxidase complex.
Study Information
pubmed
2005
2005-09-01T00:00:00.000Z
10.1111/j.1462-5822.2005.00549.x
139
77