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 alpha-defensins were analysed by enzyme-linked immunosorbent assay, and real-time polymerase chain reaction (PCR) was used to quantify alpha-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 alpha-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.
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 alpha-defensins were analysed by enzyme-linked immunosorbent assay, and real-time polymerase chain reaction (PCR) was used to quantify alpha-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 MAPKp38 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 alpha-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.
Authors: Lydia R Coulthard; Danielle E White; Dominic L Jones; Michael F McDermott; Susan A Burchill Journal: Trends Mol Med Date: 2009-08-06 Impact factor: 11.951
Authors: Nina M van Sorge; Federico C Beasley; Ivan Gusarov; David J Gonzalez; Maren von Köckritz-Blickwede; Sabina Anik; Andrew W Borkowski; Pieter C Dorrestein; Evgeny Nudler; Victor Nizet Journal: J Biol Chem Date: 2013-01-15 Impact factor: 5.157