IngentaConnect Cathelicidin LL-37 induces the generation of reactive oxygen spec...

Abstract:

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 Ca²⁺ 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 Ca²⁺ 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.

Keywords: cathelicidin LL-37; α-defensin; mitogen-activated protein kinase; neutrophil; reactive oxygen species

Document Type: Research article

DOI: 10.1111/j.1365-2133.2007.08196.x

Affiliations: 1: Atopy (Allergy) Research Center 2: Host Defense and Biochemical Research 3: Departments of Dermatology

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Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human α-defensins from neutrophils