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

Abstract

Cathelicidins and other antimicrobial peptides are deployed at epithelial surfaces to defend against infection. These molecules have broad-spectrum killing activity against microbes and can have effects on specific mammalian cell types, potentially stimulating additional immune defense through direct chemotactic activity or induction of cytokine release. In humans, the cathelicidin hCAP18/LL-37 is processed to LL-37 in neutrophils, but on skin it can be further proteolytically processed to shorter forms. The influence of these cathelicidin peptides on keratinocyte function is not known. In the current study, DNA microarray analysis and confirmatory protein analysis showed that LL-37 affects the expression of several chemokines and cytokines by keratinocytes. Analysis of a synthetic peptide library derived from LL-37 showed that antimicrobial activity against bacterial, fungal, and viral skin pathogens resides within specific domains of the parent peptide, but antimicrobial activity does not directly correlate with the ability to stimulate IL-8 production in keratinocytes. IL-8 release was induced by d- and l-amino acid forms of cathelicidin and correlated with membrane permeability, suggesting that highly structure-specific binding to a cell surface receptor is not likely. However, this effect was inhibited by either pertussis toxin or AG1478, an epidermal growth factor receptor tyrosine kinase inhibitor, suggesting that cathelicidin may indirectly stimulate multiple signaling pathways associated with cell surface receptors. Taken together, these observations suggest that proteolytic processing may alter the balance between cathelicidin antimicrobial and host immunostimulatory functions.

Cathelicidins in inflammation and tissue repair: Potential therapeutic applications for gastrointestinal disorders

“…The findings by Braff et al [19] show that LL-37 promotes the mRNA expression of numerous inflammatory mediators, including IL-8, cyclooxygenase-2 (COX-2), pro-IL-1β, and IL-6 by keratinocytes. The ability of LL-37 to increase pro-inflammatory mediators released from keratinocytes may have a critical impact on the initial phase of cutaneous inflammation.…”

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

“…It has direct microbicidal activities against a wide range of bacteria, viruses, fungi, and protozoa in vitro (5)(6)(7)(8)(9)(10). In addition, its antimicrobial functions in vivo are significantly contributed by multiple immunomodulatory properties (11)(12)(13). The physiological importance of cathelicidin in host defense is underscored by the increased susceptibility of the knock-out animals, whereas the transgenics develop resistance to various infections (14 -18).…”

Cathelicidin Antimicrobial Peptides Block Dendritic Cell TLR4 Activation and Allergic Contact Sensitization

“…Under cell culture conditions LL-37 has also been shown to stimulate chemokine and cytokine secretion from monocytes, dendritic cells (DC), 3 and epithelial keratinocytes (10), but recent data have also shown that LL-37 can inhibit LPS induced cytokine release from monocytes (11). Given that 1) LL-37 could mediate both proinflammatory and anti-inflammatory effects in vitro and 2) the degree of proteolytic processing (12,13) of cathelicidin peptides in tissue dictates function (10), it has remained unclear what effects cathelicidins or other antimicrobial peptides may have on inflammation in vivo.…”