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Cathelicidin LL‐37 induces the generation of reactive oxygen species and release of human α‐defensins from neutrophils
Author(s) -
Zheng Y.,
Niyonsaba F.,
Ushio H.,
Nagaoka I.,
Ikeda S.,
Okumura K.,
Ogawa H.
Publication year - 2007
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/j.1365-2133.2007.08196.x
Subject(s) - atopy , allergy , atopic dermatitis , cathelicidin , medicine , immunology , innate immune system , immune system
Summary Background Psoriasis is characterized by epidermal infiltration of neutrophils that destroy invading microorganisms via a potent antimicrobial arsenal of oxidants and antimicrobial agents. In contrast to atopic dermatitis, psoriasis exhibits low levels of skin infections due to the presence of antimicrobial agents, including cathelicidin LL‐37. LL‐37 kills a broad spectrum of microbes, and activates neutrophil chemotaxis. Objective To determine whether or not LL‐37 could regulate additional neutrophil functions such as production of cytokines/chemokines, reactive oxygen species and release of neutrophil antimicrobial peptides. Methods Human peripheral blood neutrophils were used in this study. The production of interleukin (IL)‐8 and release of α‐defensins were analysed by enzyme‐linked immunosorbent assay, and real‐time polymerase chain reaction (PCR) was used to quantify α‐defensin gene expression. Phosphorylation of mitogen‐activated protein kinase (MAPK) was determined by Western blotting. The generation of reactive oxygen species was examined using flow cytometry, and intracellular Ca 2+ mobilization was measured using a calcium assay kit. Results LL‐37 enhanced the production of IL‐8 under the control of MAPK p38 and extracellular signal regulated kinase (ERK), as evidenced by the inhibitory effects of p38 and ERK1/2 inhibitors on LL‐37‐mediated IL‐8 production. Furthermore, LL‐37 induced phosphorylation of p38 and ERK. We also revealed that LL‐37 stimulated the generation of reactive oxygen species dose‐ and time‐dependently, most probably via NADPH oxidase activation and intracellular Ca 2+ mobilization. Finally, LL‐37 induced both mRNA expression and protein release of α‐defensins, known as human neutrophil peptide 1–3. Conclusion Taken together, we suggest that in addition to its microbicidal properties, LL‐37 may contribute to innate immunity by enhancing neutrophil host defence functions at inflammation and/or infection sites.