However, in contrast to learn more our observations, the LL-37 induced apoptosis via caspase-3 activation; these data indicate caspase-dependent programmed cell death. Importantly, this peptide suppressed the apoptosis of neutrophils [94]. In this context, the mechanisms involved in the apoptotic and antiapoptotic

actions of these peptides remain to be determined. Taken together, these studies show that the mechanism of tumor cell killing by host defense peptides is poorly understood. However, in particular, human cathelicidin peptides have selective cytotoxicity toward tumor cells and may be useful antitumor therapeutic agents. A previous study showed that LL-37 protects against endotoxin shock [95]. Lipopolysaccharide (LPS) is a cell membrane component of gram-negative bacteria. LPS has strong biological activity and plays a key role in the pathogenesis of endotoxin shock associated with various syndromes [96] and [97]. LPS induces monocytes, macrophages, and other types of cells to produce and release potent pro-inflammatory cytokines. However, LL-37 can

neutralize the biological activity of LPS by binding to it with higher affinity [98], [99] and [100]. Indeed, we found that the LL-37-derived 27-mer synthetic peptide (hCAP18109–135) suppressed development of endotoxin-induced uveitis in vivo in rats [101]. Therefore, the hCAP18109–135 suppresses the onset of LPS-triggered inflammatory reactions by binding directly to LPS. LL-37 demonstrates chemotactic activity buy GW786034 for T lymphocyte cells, monocytes, and neutrophils [102], thus attracting even more leukocytes

to the site of increased LL-37 concentration in inflamed or infected tissue. In addition, mast cells, which form an important tissue-localized part of innate immunity, exhibited LL-37-induced migration, histamine release, and intracellular Ca2+ mobilization [103]. LL-37 was proven to activate at least three different receptors, namely FPRL-1 (formyl peptide receptor-like 1) [102] and [103], EGFR (epidermal growth factor receptor) [104], and the purinegic receptor P2X7[105]. Furthermore, a vitamin D responsive element is identified in the human cathelicidin gene CAMP promoter region [106]. CYTH4 The vitamin D3 signaling cascade that leads to increased cathelicidin expression has been identified [107] and [108]. LL-37 modulates dendritic cell (DC) differentiation and enhances the secretion of helper T cell type 1 (Th-1)-inducing cytokines in vitro [109]. These results suggest that hCAP18/LL-37 bridges the innate and adaptive immune responses. Recently, the hCAP18/LL-37 peptide has been identified as the key factor that mediates the activation of plasmacytoid dendritic cells (pDCs) in psoriasis, a common autoimmune skin disease. pDCs do not normally respond to self-DNA, but binding to hCAP18/LL-37 converted DNA into a potent stimulus for pDC activation. The hCAP18/LL-37 and self-DNA complexes signaled through TLR9 and elicited interferon (IFN)-α release from pDCs.