Postsecretory Processing Generates Multiple Cathelicidins for Enhanced Topical Antimicrobial Defense

Abstract

The production of antimicrobial peptides and proteins is essential for defense against infection. Many of the known human antimicrobial peptides are multifunctional, with stimulatory activities such as chemotaxis while simultaneously acting as natural antibiotics. In humans, eccrine appendages express DCD and CAMP, genes encoding proteins processed into the antimicrobial peptides dermcidin and LL-37. In this study we show that after secretion onto the skin surface, the CAMP gene product is processed by a serine protease-dependent mechanism into multiple novel antimicrobial peptides distinct from the cathelicidin LL-37. These peptides show enhanced antimicrobial action, acquiring the ability to kill skin pathogens such as Staphylococcus aureus and Candida albicans. Furthermore, although LL-37 may influence the host inflammatory response by stimulating IL-8 release from keratinocytes, this activity is lost in subsequently processed peptides. Thus, a single gene product encoding an important defense molecule alters structure and function in the topical environment to shift the balance of activity toward direct inhibition of microbial colonization.

Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic

“…4), we may speculate that one form originates from immune cells and the other from epithelial cells; however, this speculation will require further studies to substantiate. It has recently been reported that several processing forms of the human cathelicidin are generated in sweat, resulting in several active peptides with a different spectrum of antibacterial activity (26).…”

Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities

“…The human cathelicidin antimicrobial peptide LL-37 has been implicated in a variety of effects on the host immune system, including chemotaxis (16,19), dendritic cell differentiation (17), and cytokine release (22). Epithelial surfaces such as the skin are exposed to abundant levels of LL-37 during the response to injury or infection.…”

“…In sweat, three additional forms have been found: KR-20, a 20-aa derivative; RK-31, a 31-aa derivative; and KS-30, a 30-aa derivative. All three processed peptides exhibit an overall gain in antimicrobial activity compared with full-length LL-37 (22). The importance of processing human cathelicidin from LL-37 as the form first released from neutrophils to smaller peptide fragments is unclear.…”

Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application

“…The peptide solutions were diluted 1:100 with acetonitrile/ water/TFA 50/50/0.2 (v/v/v) and 1 ml of each solution was mixed with 1 ml of a 10 mg/ml solution of a-cyano-4-hydroxycinnamic acid (4-ACH) in acetonitrile/water/TFA 50/50/0.2 (v/v/v) containing a mass reference peptide (VNTPEHVV-PYGLGSPSRS, bovine big-endothelin (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), MH av + = 1897.10).…”