Host defense peptide LL-37, in synergy with inflammatory mediator IL-1β, augments immune responses by multiple pathways

Jie Yu, Neeloffer Mookherjee, Kathleen Wee, Dawn M.E. Bowdish, Jelena Pistolic, Yuexin Li, Linda Rehaume, Robert Hancock

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

The human cathelicidin LL-37 is a cationic host defense peptide and serves as an important component of innate immunity. It has been demonstrated to be a multifunctional modulator of innate immune responses, although the mechanism(s) underlying this have not been well characterized. In this study, it was demonstrated that LL-37 synergistically enhanced the IL-1β-induced production of cytokines (IL-6, IL-10) and chemokines such as macrophage chemoattractant proteins (MCP-1, MCP-3) in human PBMC, indicating a role in enhancing certain innate immune responses. Similarly, LL-37 synergistically enhanced chemokine production in the presence of GM-CSF, but IFN-γ, IL-4, or IL-12 addition led to antagonism, indicating that the role of LL-37 in reinforcing specific immune responses is selective and restricted to particular endogenous immune mediators. The inhibition of G protein-coupled receptors and PI3K substantially suppressed the ability of IL-1β and LL-37 to synergistically enhance the production of chemokine MCP-3. Consistent with this, the combination of IL-1β and LL-37 enhanced the activation/phosphorylation of kinase Akt and the transcription factor CREB. The role of transcription factor NF-κB was revealed through the demonstration of enhanced phosphorylation of IκBα and the consequent nuclear translocation of NF-κB subunits p50 and p65, as well as the antagonistic effects of an inhibitor of IκBα phosphorylation. These results together indicate that the human host defense peptide LL-37 can work in synergy with the endogenous inflammatory mediator IL-1β to enhance the induction of specific inflammatory effectors by a complex mechanism involving multiple pathways, thus reinforcing certain innate immune responses.

LanguageEnglish
Pages7684-7691
Number of pages8
JournalJournal of Immunology
Volume179
Issue number11
Publication statusPublished - 1 Dec 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this