Human Cathelicidin CAP18/LL-37 Changes Mast Cell Function toward Innate Immunity

Abstract

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.