Antimicrobial Peptides Human β-Defensins and Cathelicidin LL-37 Induce the Secretion of a Pruritogenic Cytokine IL-31 by Human Mast Cells

Abstract

In addition to their microbiocidal properties, human β-defensins (hBDs) and cathelicidin LL-37 stimulate a number of mammalian cell activities, including migration, proliferation, and cytokine/chemokine production. Because hBDs and LL-37 cause mast cells to release pruritogens such as histamine and PGs, we hypothesized that these peptides would stimulate the secretion of a novel pruritogenic mediator IL-31, predominantly produced by T cells. hBDs and LL-37 enhanced IL-31 gene expression and IL-31 protein production and release in the human mast cell line LAD2, as well as in peripheral blood-derived cultured mast cells, suggesting that mast cells are another source of IL-31. Moreover, the expression of IL-31 was elevated in psoriatic skin mast cells, and hBD-2–4 and LL-37, but not hBD-1, enhanced its expression in vivo in rat skin mast cells. hBDs and LL-37 also induced the release of other pruritogenic mediators, including IL-2, IL-4, IL-6, GM-CSF, nerve growth factor, PGE2, and leukotriene C4, and increased mRNA expression of substance P. hBD– and LL-37–mediated IL-31 production/release was markedly reduced by pertussis toxin and wortmannin, inhibitors of G-protein and PI3K, respectively. As evidenced by the inhibitory effects of MAPK-specific inhibitors, hBD-2–4 and LL-37 activated the phosphorylation of MAPKs p38, ERK, and JNK that were required for IL-31 production and release. The ability of hBDs and LL-37 to stimulate the production and release of IL-31 by human mast cells provides a novel mechanism by which skin-derived antimicrobial peptides/proteins may contribute to inflammatory reactions and suggests a central role of these peptides in the pathogenesis of skin disorders.

GATA2 Is a Critical Transactivator for the Human IL1RL1/ST2 Promoter in Mast Cells/Basophils

“…Cells-The LAD2 (human mast cell leukemia; a kind gift from Dr. Arnold Kirshenbaum) (12) and KU812 (human basophilic leukemia) cell lines were maintained as described previously (13,14). Human basophils were purified from the peripheral blood of volunteers using the MACS separation system with a basophil isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) as described (15).…”

Cathelicidin – Its Structure, Function and the Role in Autoimmune Diseases

“…The cathelicidin molecule was discovered in 1995 [37,40,50]. Once isolated from the neutrophils, the bovine Bac5 peptide was observed to come from inactive precursors.…”

“…Due to their amphipathic structure, they both show direct affinity for bacterial cell membranes, as well as they participate in the effector mechanisms of the acquired immunity through the recruitment and stimulation of various cells. This correlates with the peptide's double nature: of a peptide antibiotic and of a signal cell [37,48,50]. Cathelicidin is detected e.g.…”

“…Once isolated from the neutrophils, the bovine Bac5 peptide was observed to come from inactive precursors. Cloning of the precursor-coding cDNA proved that the proteins bind to each other forming a mature peptide [37]. Cathelicidin was first described in leukocytes and the cell nucleus, and subsequently it was discovered in other cells and tissues: granulocytes, keratinocytes, monocytes [48,50], as well as in skin, intestine and pulmonary epithelium [32,51].…”

“…It contains: a signal peptide composed of 30 amino-acids, 99-144 amino-acid cathelin domain and AMPs composed of 12-100 amino-acids [37,40,50]. The hCAP-18 propeptide is synthesised in the bone marrow and stored in mature neutrophils, lymphocytes' subpopulation and monocytes.…”