Human cathelicidin CAP18/LL-37 changes mast cell function toward innate immunity.
The antimicrobial peptide LL-37 is generated from skin keratinocytes during infection of Gram-negative bacteria and exerts a microbicidal effect. LL-37 also causes functional changes in mast cells. Mast cells in the skin are involved in the innate immune system response against microbial infections via Toll-like receptors (TLRs), such as TLR4, which that is known to recognize lipopolysaccharide (LPS), a bacterial component. Thus, in the present study, we examined the effects of LL-37 on the expression of TLRs and the generation of cytokines on mast cells, and considered functional changes in the host defense system against bacteria. We observed that LL-37 increased the level of TLR4 mRNA and TLR4 protein, and that LL-37 induced the release of IL-4, IL-5 and IL-1beta from mast cells. Cross-interaction between LL-37-triggered TLR4 augmentation and LL-37-inducible cytokine generation was also examined. Although the up-regulation of LL-37-inducible Th2 cytokines was cancelled by LPS, the augmentation of pro-inflammatory cytokine production was still observed. These findings indicate that LL-37 co-existing with the bacterial component switches mast cell function and directs human mast cells toward innate immunity. In conclusion, LL-37 may be a candidate modifier of the host defense against bacterial entry by serving as an alarm for sentinels such as mast cells.
Yoshioka
Mino
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Fukuishi
Nobuyuki
N
Kubo
Yuichi
Y
Yamanobe
Hiroyuki
H
Ohsaki
Kanae
K
Kawasoe
Yoshiko
Y
Murata
Mana
M
Ishizumi
Aya
A
Nishii
Yumiko
Y
Matsui
Nobuaki
N
Akagi
Masaaki
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D047468:Immunoprecipitation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D054804:Cathelicidins
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D018925:Chemokines; D016207:Cytokines; D018076:DNA, Complementary; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D001619:beta-N-Acetylhexosaminidases; D054804:Cathelicidins