Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses
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E. Margo Molhoek
Abstract
Cathelicidins are effector molecules of the innate host defense system that establish an antimicrobial barrier at epithelial interfaces. The human cathelicidin LL-37, in addition to its antimicrobial activity, also exhibits immunomodulatory effects, such as inhibition of pro-inflammatory responses to bacterial LPS in human monocytic cells. In this report, we demonstrate that LL-37 almost completely prevents the pro-inflammatory cytokine release by human peripheral blood mononuclear cells (PBMCs) following stimulation with Toll-like receptor (TLR)4 and TLR2/1 agonists while leaving TLR2/6, TLR5, TLR7 and TLR8 responses unchanged. Modulation of the TLR response by LL-37 occurred at least partly through the MAP kinase pathway via inhibition of p38 phosphorylation. By using an LL-37 library with overlapping sequences, we identified the mid-region of LL-37, comprising amino acids 13–31, as the active domain for the modulation of TLR responses. The mechanism of immunomodulation of LL-37 and LL-37 fragments is lipopoly-saccharide binding. Correlations between the capacity of LL-37 fragments to modulate TLR responses and their physico-chemical properties revealed that cationicity and hydrophobicity are essential for the modulation of LL-37-mediated TLR responses.
©2009 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- Minireview
- Central nervous system: cholesterol turnover, brain development and neurodegeneration
- Protein Structure and Function
- Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses
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- Human CYP4Z1 catalyzes the in-chain hydroxylation of lauric acid and myristic acid
- Flavivirus NS5 associates with host-cell proteins zonula occludens-1 (ZO-1) and regulating synaptic membrane exocytosis-2 (RIMS2) via an internal PDZ binding mechanism
- Membranes, Lipids, Glycobiology
- Co-expression of 9-O-acetylated sialoglycoproteins and their binding proteins on lymphoblasts of childhood acute lymphoblastic leukemia: an anti-apoptotic role
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- Molecular Medicine
- Amidinoanthracyclines – a new group of potential anti-hepatitis C virus compounds
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- Staphylococcal cysteine protease staphopain B (SspB) induces rapid engulfment of human neutrophils and monocytes by macrophages
- A completed KLK activome profile: investigation of activation profiles of KLK9, 10, and 15
