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The human cationic host defense peptide LL-37 modulates neutrophil apoptosis and chemokine responses

University of British Columbia

LL-37 is a human cationic peptide expressed primarily by neutrophils and epithelial cells. It is a 37 amino acid peptide that belongs to the cathelicidin family of the cationic host defense peptides. Accumulating evidence has demonstrated that LL-37 has multiple immunomodulatory properties. The modulatory effects of LL-37 on neutrophils were investigated here, and LL-37 was shown to be a potent inhibitor of spontaneous apoptosis in human neutrophils, signalling through P2X₇ receptors and G-protein-coupled receptors other than the formyl peptide receptor-like- 1 molecule. Inhibition of neutrophil apoptosis involved modulation of Mcl-1 expression, inhibition of BID and procaspase-3 cleavage, and the activation of phosphatidylinositol-3 kinase and protein kinase C but not the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2) pathway. In addition, LL-37 modified neutrophil cytokine/chemokine responses to pro-inflammatory stimuli in a stimulus-specific manner. Specifically, LL-37 abrogated LPS-induced TNF-a cytokine production while enhancing IL-1β elicited release of TNF-a as well as a number of chemokines including IL-8, Gro-a, CCL-22 and Mip-la . The increased release of chemokines induced synergistically by LL-37 and IL-1β resulted from de novo protein synthesis and was found to be associated with the signalling through the ERK1/2 and p38 MAP kinases and nuclear factor κΒ pathways. These novel immunomodulatory properties of LL-37 may contribute to peptide-mediated enhancement of innate host defenses against acute infection and are of considerable significance in the development of such peptides and their synthetic analogs as potential therapeutics for use against multiple antibiotic-resistant infectious diseases.

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2011-02-24

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http://hdl.handle.net/2429/31726

Microbiology and Immunology

University of British Columbia

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