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LL-37, a human host defense peptide with immunomodulatory properties Bowdish, Dawn Marie Edith

Abstract

Human cationic antimicrobial protein-18 (hCAP-18) is the sole human cathelicidin. It is found at high concentrations in the specific granules of neutrophils, is modestly expressed by epithelial and other cells and can be induced during the course of infection and/or inflammation. The mature, extracellular form of hCAP-18 is termed LL-37, which is a positively-charged, 37-amino acid peptide. Neutrophil-derived host defence peptides were initially discovered as components of the non-oxidative killing mechanisms of neutrophils; however, it is unclear whether LL-37 kills bacteria directly at mucosal surfaces where it is found at lower concentrations. I demonstrated that although LL-37 is antimicrobial in vitro under low salt conditions, it has little or no antimicrobial activity in media containing physiologically relevant cation concentrations. Thus I hypothesised that direct antimicrobial activity was probably not its primary function in vivo at mucosal surfaces. The immunomodulatory properties of LL-37 were investigated in tissue culture media which contains physiological concentrations of cations. When monocytes were treated with LL-37, lipopolysaccharide (LPS)-induced production of proinflammatory cytokines was blocked but TNF-α- induced cytokine production was unaffected and IL-1β-induced cytokine production was enhanced. Consistent with this observation, LL-37 was able to block LPS-induced translocation of the p65 subunit of the pro-inflammatory transcription factor, NF-KB. Other early signalling events mediated by LL-37 included activation of two mitogen-activated protein kinases, p38 and extracellular-regulated kinase. The activation of these kinases was required for IL-8 transcription and release as well as transcription of the chemokines MIP-1α, MIP-1β, and MCP-1. The activation of these kinases and subsequent production and release of IL-8 could be synergistically increased by the presence of granulocyte macrophage-colony stimulating factor, but not related cytokines, indicating that the composition of the inflammatory milieu may affect monocyte responses to LL-37. The data presented here demonstrate that LL-37 is a multi-functional immunomodulator with both pro- and antiinflammatory properties which are maintained at physiological cation concentrations. The observation that LL-37 induced chemokines production suggests that it may recruit leukocytes to sites of infection or inflammation thus providing a possible explanation for the observed antimicrobial properties of this peptide in vivo.

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