Diseases: Deficiency in saliva LL-37 accords with occurrence of periodontal disease in patients with morbus Kostmann Pütsep K et al., 2002. Lower levels of LL-37 in serum are correlated with RSV and severity of bronchiolitis and viral etiology (Mansbach et al., 2017). The relationship of human LL-37 with cancer is complex (Reviewed by Wu et al. 2010). While LL-37 could promote cancer metastasis in certain cases, its fragment (FK-16) have been documented to have anti-cancer effects (Li et al., 2006).
Discovery: molecular formula of LL-37: C205H341N59O53; Mol. Wt. 4493.312; molar extinction coefficient = 0. Discovered in 1995 by three labs (see the ref; Cowland JB et al. 1995; Larrick JW et al. 1995). The precursor protein is human cationic antimicrobial protein-18 kDa (hCAP-18). The mature peptide released by proteinase 3 is referred to as LL-37 (Gudmundsson GH et al., 1996), which is two residues shorter than the predicted form FALL-39 (old).
Activity: Active against bacteria (E. coli. B. thailandensis, A. baunmannii, H. pylori, K. pneumoniae, H. influenzae, P. gingivalis, Y. pestis, B. anthracis, E. faecalis, S. aureus, S. mutans, M. tuberculosis (anti-TB), M. smegmatis, M. bovis, L. casei, L. monocytogenes, M. luteus, P. acnes, T. denticola, T. palidum, Y. pestis, A. xylosoxidans, B. suis, F. novicida, F. nucleatum, L. interrogans, Group A streptococcus, Group B streptococcus), fungi (C. albicans), viruses (HIV-1; Herpes Simplex Virus , HSV-1; respiratory syncytial virus, RSV; influenza virus; human adenovirus, HAdV; dengue virus type 2 (DENV-2)), Zika virus; the Kaposi's sarcoma-associated herpesvirus (KSHV) (Brice et al., 2018); Venezuelan equine encephalitis virus (VEEV) (Ahmed A et al. 2019); parasites (e.g., E. histolytica), cancer cells. It inhibits F. novicida biofilms in vitro even at 0.24 ug/ml based on CV staining (Amer LS et al., 2010) (EC50 50 nM). It inhibits biofilm formation of P. aeruginosa below MIC (0.05 ug/ml) (Overhage J et al., 2008;Dean SN et al., 2011). It can also kill sperms, a possible spermicidal agent for developing a potential vaginal contraceptive (Srakaew N et al., 2014). It shows synergistic effect with defensins or lysozyme.
Structure: At an acidic condition, LL-37 is disordered, but becomes tetramer (involving residues 2-36) at elevated pH (~7) (Li et al., 2007). This tetramer is maintained in zwitterionic membranes but dissociated in anionic bacterial membranes (Oren et al. 1999 Biochem J 341:501-513). Upon association with bacterial outer membrane component LPS or inner membrane component PG, LL-37 adopts a long helix covering residues 2-31 with a disordered C-terminal tail. The membrane-bound high-resolution structure of LL-37 is determined by 3D NMR in the presence of SDS or D8PG using 13C,15N-labeled sample (Wang G, 2008). You can rotate, zoom, and view the 3D structure here in the PDB.
Sunlight and vitamin D are good: The expression of LL-37 is transcriptionally regulated by vitamin D (Karlsson J et al. 2008), sunlight, and other factors. The administration of vitamin D (25D3) as supplement (leading to cathelicidin expression in epithelial cells) may prevent unitary tract infection (UTI) (Hertting, O et al. 2010). Other AMP inducing factors are listed here.
Beyond antimicrobials: In addition to antimicrobial and anti-septic effects, LL-37 also possesses multiple other functions such as chemotaxis (e.g. to monocytes; T cells; peripheral blood neutrophils; eosinophils) via formyl peptide receptor 2 (FPR2) (Yang D et al., 2000), mast cells via MrgX2 (Subramanian et al., 2011), activates CXCR2 receptor of neutrophils, purinergic receptor P2X7 in fibroblasts, and insulin growth factor receptor in epithelial cells, promotes wound healing, cell differentiation, apoptosis, and immune modulation. LL-37 can also associate with human apolipoprotein A-I, F-actin and DNA and becomes inactive (reviewed by Wang, G 2007). The binding of LL-37 to LPS modulates the signal transduction via the TLR4 pathway, while its binding to bacterial DNA works via the TLR9 pathway.
Post-translational modification: Arginines of LL-37 can get citrullinated (Kilsgård et al., 2012), weakening its ability in preventing endotoxin-induced sepsis (Koziel J et al., 2014). Also, up to four out of the five arginines of LL-37 can be ADP-ribosylated, thereby regulating peptide properties in vivo (Picchianti et al., 2015). LL-37 may also be carbamylated (Koro et al., 2016). LL-37 can be cleaved by multiple proteases such as cathepsins S and K. However, it inhibits cathepsin L (Andrault PM et al., 2015).
Surface immobilization: LL-37 has also been covalently immobilized 2006 Gabriel M et al. to the titanium surface. So are KR-12 (the minimal antimicrobial peptide), IG-25 that corresponds to residues 13-37 of LL-37, and the major antimicrobial region FK-16 (GF-17 minus N-terminus G) (Mishra and Wang, 2017).
The LL-37 story will surely continue to evolve. Found in multiple species. Also see ALL-38. APD update 12/2010; 11/2011; 2/2012; 8/2012; Jan2013; 4/2013; 5/2014; 9/2014; Jan2015; 12/2015; 2/2016; 4/2016; 10/2016; 3/2017; 6/2017; 8/2017; 12/2017; Jan2018; 8/2018; 10/2018; 2/2019; 9/2019 GW.
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