Cathelicidin-related antimicrobial peptides are a family of polypeptides primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs).[1] Cathelicidins serve a critical role in mammalian innate immune defense against invasive bacterial infection.[2] The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous.[2]
Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain.[2]
Cathelicidin peptides have been isolated from many different species of mammals. Cathelicidins were originally found in neutrophils, but have since been found in many other cells including epithelial cells and macrophages after activation by bacteria, viruses, fungi, or the hormone 1,25-D, which is the hormonally active form of vitamin D.[3] The protein encoded by the human cathelicidin gene, CAMP, is cleaved into the LL-37 peptide, which has several immunological functions.
Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures.[4] Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures.[2]
The cathelicidin family shares primary sequence homology with the cystatin[5] family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.
Mechanism of antimicrobial activity
The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active.[6]
Mammalian orthologs
Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, and horses.
Currently identified cathelicidins include the following:[2]
NOTE: This article seems to be split between two pages. More about cathelicidin's clinical significance can be found on the page for its encoding gene, LL-37.
Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea.[11] Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.[12]
Higher plasma levels of human cathelicidin antimicrobial protein (hCAP18), which are up-regulated by vitamin D, appear to significantly reduce the risk of death from infection in dialysis patients. Patients with a high level of this protein were 3.7 times more likely to survive kidney dialysis for a year without a fatal infection.[13]
Vitamin D up-regulates genetic expression of cathelicidin, which exhibits broad-spectrum microbicidal activity against bacteria, fungi, and viruses.[14][15] Cathelicidin rapidly destroys the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages.
↑Zaiou M, Nizet V, Gallo RL (May 2003). "Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence". The Journal of Investigative Dermatology. 120 (5): 810–6. doi:10.1046/j.1523-1747.2003.12132.x. PMID12713586.
↑Gallo RL, Kim KJ, Bernfield M, Kozak CA, Zanetti M, Merluzzi L, Gennaro R (May 1997). "Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse". The Journal of Biological Chemistry. 272 (20): 13088–93. doi:10.1074/jbc.272.20.13088. PMID9148921.
↑Hao X, Yang H, Wei L, Yang S, Zhu W, Ma D, Yu H, Lai R (August 2012). "Amphibian cathelicidin fills the evolutionary gap of cathelicidin in vertebrate". Amino Acids. 43 (2): 677–85. doi:10.1007/s00726-011-1116-7. PMID22009138.
Dürr UH, Sudheendra US, Ramamoorthy A (September 2006). "LL-37, the only human member of the cathelicidin family of antimicrobial peptides". Biochimica et Biophysica Acta. 1758 (9): 1408–25. doi:10.1016/j.bbamem.2006.03.030. PMID16716248.
Chromek M, Slamová Z, Bergman P, Kovács L, Podracká L, Ehrén I, Hökfelt T, Gudmundsson GH, Gallo RL, Agerberth B, Brauner A (June 2006). "The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection". Nature Medicine. 12 (6): 636–41. doi:10.1038/nm1407. PMID16751768.
Gombart AF, Borregaard N, Koeffler HP (July 2005). "Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3". FASEB Journal. 19 (9): 1067–77. doi:10.1096/fj.04-3284com. PMID15985530.
López-García B, Lee PH, Gallo RL (May 2006). "Expression and potential function of cathelicidin antimicrobial peptides in dermatophytosis and tinea versicolor". The Journal of Antimicrobial Chemotherapy. 57 (5): 877–82. doi:10.1093/jac/dkl078. PMID16556635.
Lehrer RI, Ganz T (January 2002). "Cathelicidins: a family of endogenous antimicrobial peptides". Current Opinion in Hematology. 9 (1): 18–22. doi:10.1097/00062752-200201000-00004. PMID11753073.
Niyonsaba F, Hirata M, Ogawa H, Nagaoka I (September 2003). "Epithelial cell-derived antibacterial peptides human beta-defensins and cathelicidin: multifunctional activities on mast cells". Current Drug Targets. Inflammation and Allergy. 2 (3): 224–31. doi:10.2174/1568010033484115. PMID14561157.
van Wetering S, Tjabringa GS, Hiemstra PS (April 2005). "Interactions between neutrophil-derived antimicrobial peptides and airway epithelial cells". Journal of Leukocyte Biology. 77 (4): 444–50. doi:10.1189/jlb.0604367. PMID15591123.
Cowland JB, Johnsen AH, Borregaard N (July 1995). "hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules". FEBS Letters. 368 (1): 173–6. doi:10.1016/0014-5793(95)00634-L. PMID7615076.
Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B, Salcedo R (June 1996). "The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes". European Journal of Biochemistry. 238 (2): 325–32. doi:10.1111/j.1432-1033.1996.0325z.x. PMID8681941.
Larrick JW, Lee J, Ma S, Li X, Francke U, Wright SC, Balint RF (November 1996). "Structural, functional analysis and localization of the human CAP18 gene". FEBS Letters. 398 (1): 74–80. doi:10.1016/S0014-5793(96)01199-4. PMID8946956.
Frohm M, Agerberth B, Ahangari G, Stâhle-Bäckdahl M, Lidén S, Wigzell H, Gudmundsson GH (June 1997). "The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders". The Journal of Biological Chemistry. 272 (24): 15258–63. doi:10.1074/jbc.272.24.15258. PMID9182550.
Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, Heumann D (September 2001). "Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells". Journal of Immunology. 167 (6): 3329–38. doi:10.4049/jimmunol.167.6.3329. PMID11544322.
Giuliani A, Pirri G, Nicoletto S (2007). "Antimicrobial peptides: an overview of a promising class of therapeutics". Cent. Eur. J. Biol. 2 (1): 1–33. doi:10.2478/s11535-007-0010-5.
Burton MF, Steel PG (December 2009). "The chemistry and biology of LL-37". Natural Product Reports. 26 (12): 1572–84. doi:10.1039/b912533g. PMID19936387.
