The Expression of the Gene Coding for the Antibacterial Peptide LL-37 Is Induced in Human Keratinocytes during Inflammatory Disorders

Abstract

The epithelia constitute a major barrier to the environment and provide the first line of defense against invading microbes. Antimicrobial peptides are emerging as participants in the defense system of epithelial barriers in general. Originally we isolated the human antimicrobial peptide LL-37 from granulocytes. The gene (CAMP or cathelicidin antimicrobial peptide) coding for this peptide belongs to the cathelicidin family, whose members contain a conserved pro-part of the cathelin type. The human genome seems to have only one gene of this family, whereas some mammalian species have several cathelicidin genes. In the present work we demonstrate up-regulation of this human cathelicidin gene in inflammatory skin disorders, whereas in normal skin no induction was found. By in situ hybridization and immunohistochemistry the transcript and the peptide were located in keratinocytes throughout the epidermis of the inflammatory regions. In addition, the peptide was detected in partially pure fractions derived from psoriatic scales by immunoblotting. These fractions also exhibited antibacterial activity. We propose a protective role for LL-37, when the integrity of the skin barrier is damaged, participating in the first line of defense, and preventing local infection and systemic invasion of microbes.Epithelia provide a barrier between the body and the environment. In addition, the epithelial cells have an active immunological role with antigen processing and presentation and production of cytokines and defense effector molecules such as microbicidal peptides. Thus, the epithelia mediate an active protection against invading microbes (1).Several broad spectrum microbicidal peptides have been identified in mammalian mucosal epithelium; bovine tracheal mucosa produces a ␤-defensin, TAP (tracheal antimicrobial peptide) (2), paneth cells of the gastrointestinal mucosa of human and mouse synthesize defensins (3, 4), and another ␤-defensin, LAP (lingual antimicrobial peptide) is expressed by bovine tongue epithelial cells (5). Thus, peptide antibiotics appear at the surface epithelium where they are likely to act as key components in the first line of defense and in the wound healing process (5). So far, all mammalian antimicrobial peptides identified at the mucosal interface belong to the defensin family. Defensins are cysteine-rich peptides folded in ␤-pleated sheets with a broad activity against bacteria, enveloped viruses, fungi, and parasites (6).We have isolated a clone for a novel human antibacterial peptide and named the putative peptide FALL-39 (7). Recently the mature active peptide LL-37 (two amino acids shorter at the N terminus than the putative peptide) was isolated from granulocytes and characterized (amino acid sequence is shown in Fig. 2B) (8). The preproprotein of LL-37 has also been named human CAP18 by another group (9). In contrast to the defensins, LL-37 is a cysteine-free peptide that can adopt an amphipathic ␣-helical conformation. The preproprotein belongs to the cathelicidin protein family. The common...

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

“…This is consistent with a role for LL-37 in antimicrobial barrier protection in human and agrees with earlier reports where low constitutive expression of LL-37 was found in normal quiescent epithelium, in contrast to the pronounced expression seen in association with injury and inflammation. [7][8][9][10] Constitutive expression of antimicrobial peptides has previously been detected in various exocrine glands such as the human cathelicidin LL-37 in sweat glands, the cathelicidin CRAMP in murine salivary glands and ␤-defensins in human salivary glands. [21][22][23] Expression of human ␤-defensin-2 (hBD-2) mRNA in mammary glands was reported by Bals et al 24 in 1998 and recently other groups have found constitutive hBD-1 expression in mammary glandular tissue of nonlactating women as well as in breast tissue during lactation and in breast milk.…”

“…1,2 Extracellular proteolytic processing of the holoprotein releases the LL-37 peptide, which has broad antimicrobial activity 1,3 as well as effects on host cells mediated by the G-protein-coupled receptor, formyl peptide receptor-like 1 (FPRL1). 4,5 hCAP18 is present in leucocytes 6 and is expressed in skin and other epithelia, where it is upregulated in association with inflammation 7,8 and injury, 9,10 consistent with a role in innate barrier protection. Recently, antimicrobial proteins including cathelicidins have been proposed to play a role also in the nonspecific host defense against tumors.…”

Transient cutaneous adenoviral gene therapy with human host defense peptide hCAP-18/LL-37 is effective for the treatment of burn wound infections

“…It has been detected in leukocytes, such as neutrophils, monocytes, NK cells, gd cells, B cells and in the epithelial cells of the testis, the gastrointestinal and respiratory tracts and in inflamed skin as an inactive pro form. [10][11][12] Extracellular cleavage into a cathelinlike domain of 14.3 kDa and the 37-amino-acid-long C-terminus (LL-37) activates the pro peptide, which by its own has been identified in plasma, airway surface fluid and in wound secretions. 10,11,13 The peptide is induced by pro-inflammatory infectious stimuli and displays direct antimicrobial activity by interaction with the cell membranes of microorganisms.…”

“…[10][11][12] Extracellular cleavage into a cathelinlike domain of 14.3 kDa and the 37-amino-acid-long C-terminus (LL-37) activates the pro peptide, which by its own has been identified in plasma, airway surface fluid and in wound secretions. 10,11,13 The peptide is induced by pro-inflammatory infectious stimuli and displays direct antimicrobial activity by interaction with the cell membranes of microorganisms. 14 Primarily understood as endogenous antibiotics, HDP obtain increasing importance as multifunctional mediators in the complex responses of innate immunity.…”

Innate defences against methicillin‐resistant Staphylococcus aureus (MRSA) infection

“…LL37/hCAP18 is initially synthesized as an 18 kD protein; then during and after secretion, it is processed to the mature 5 kD peptide (37 amino acid residues) [90,91]. LL37/hCAP18 has been identified in neutrophils, monocytes, various epithelial cells, saliva, sweat glands, and other tissues [90][91][92][93][94][95][96]. The peptide has a linear form, resembling an alpha helical structure.…”