Conversely Lande [191] showed that LL-37 was able to form a complex with human DNA and to transfer the nucleic acid to the endosomes. a major role in the building of a cellular immunity involving NK cells. [34] to describe molecules made up of both a cathelin domain name and a C-terminal antimicrobial domain name. Cathelin is an acronym for cathepsin L inhibitor. The human cathelicidin has 18 kDa (hCAP-18) and is a major protein in specific granules of neutrophils [35]. It is also present in subpopulations of lymphocytes and monocytes, in squamous ZK-261991 epithelia, in epididymis [36] and in the lung [37,38]. Several resident cells of the skin like keratinocytes, mast cells or sebocytes also express hCAP-18 [39,40,41]. Plasma contains a high concentration of hCAP-18 bound to lipoproteins [42]. The pre-proregion of cathelicidins has 128-145 residues: a signal peptide with 29-30 residues and a proregion with 99-114 residues (Physique 1). This proregion shows a high intra-species identity ranging from 75 to 100% homologies between species. Four invariant cysteinyl residues in the C-terminal region of the cathelin-like domain name form two intramolecular disulfide bridges. Open in a separate window Figure 1 Structure of LL-37. From top to bottom: ZK-261991 Location of the cathelicidin gene on the human genome and its structure. Global structure of the pre-propeptide and primary structure of hCAP-18. Sequence of various fragments of LL-37 and model representing the secondary alpha-helicoidal structure of LL-37 [94]. Considering the conservation of this proregion during evolution, it might play an important biological function with respect to the maturation of the antimicrobial peptide which is the [43] reported that the cathelin domain had also potent antibacterial activity. The survive better in macrophages from mice which do not express the cathelicidin related antimicrobial peptide (CRAMP), the murine analog of LL-37, than from wild-type (WT) mice [62]. These mice are also more prone to infections of the skin by [40] or to meningococcal infections of the central nervous system [63] and to ZK-261991 infections of the urinary tract [64]. Conversely, Bals [65] demonstrated that mice overexpressing LL-37 had a lower bacterial load and reduced inflammatory response in the lung after a challenge with and eukaryotic membranes was partly addressed at the lipid level, using lipids present in both types of organisms, but which are not fully exposed to the outer membrane leaflet, such as the acidic phospholipid phosphatidylserine (PS), phosphatidylglycerol (PG) and the non-bilayer forming unsaturated phosphatidylethanolamine (PE), the latter being abundant in prokaryotes. Whereas it was initially demonstrated that similar leakage occured in zwitterionic palmitoyl-oleoyl-phosphatidyl-choline (POPC) vesicles as well as in charged palmitoyl-oleoyl-phosphatidyl serine/palmitoyl-oleoyl-phosphatidylcholine (POPS/POPC) vesicles when considering K+ permeabilization [69], further studies demonstrated a preference for negatively charged vesicles composed of palmitoyl-oleoyl-phosphatidylglycerol (POPG) as compared to neutral zwitterionic POPC vesicles when larger molecules such as calcein were considered [71]. In another study, a mixture of neutral lipids (PC/sphingomyelin/cholesterol) SCA14 (PC:SM:CHOL) seemed equally susceptible as acidic lipids phosphatidylglycerol/diphosphatidylglycerol towards a leakage assay of a mixture of 8-amino- naphthalene-1,3,6-trisulfonic acid/[71], whereas it has no such effect in the study of Morgera [70]. From theses results and others, it seems difficult at present to confirm any clear lipid preference for LL-37 that would explain a selective effect on bacteria over mammalian cells [78]. Clearly, other features of the membrane lipid composition should be taken into account, such as the presence of LPS or peptidoglycans in the bacterial wall or complex glucosaminoglycans in the case of mammalian ZK-261991 cells and perhaps the transmembrane electrical potential. Other parameters than membrane leakage could play a significant role such as lipid clustering [79] or membrane thickening effects [80]. ZK-261991 Many studies failed to show a clear discrimination in the toxic effect on prokaryotes and eukaryotes, although some LL-37 orthologues seem.
Conversely Lande [191] showed that LL-37 was able to form a complex with human DNA and to transfer the nucleic acid to the endosomes