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Biol Chem ; 390(4): 295-303, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19166322

RESUMO

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.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Receptores Toll-Like/química , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Catelicidinas , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Humanos , Ligantes , Dados de Sequência Molecular , Transdução de Sinais , Relação Estrutura-Atividade , Receptores Toll-Like/agonistas , Receptores Toll-Like/efeitos dos fármacos , Receptores Toll-Like/metabolismo
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