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

150 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

Yu, Jie ; Mookherjee, Neeloffer ; Wee, Kathleen ; Bowdish, Dawn M.E. ; Pistolic, Jelena ; Li, Yuexin ; Rehaume, Linda ; Hancock, Robert. / Host defense peptide LL-37, in synergy with inflammatory mediator IL-1β, augments immune responses by multiple pathways. In: Journal of Immunology. 2007 ; Vol. 179, No. 11. pp. 7684-7691.
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Yu, J, Mookherjee, N, Wee, K, Bowdish, DME, Pistolic, J, Li, Y, Rehaume, L & Hancock, R 2007, 'Host defense peptide LL-37, in synergy with inflammatory mediator IL-1β, augments immune responses by multiple pathways', Journal of Immunology, vol. 179, no. 11, pp. 7684-7691.

Host defense peptide LL-37, in synergy with inflammatory mediator IL-1β, augments immune responses by multiple pathways. / Yu, Jie; Mookherjee, Neeloffer; Wee, Kathleen; Bowdish, Dawn M.E.; Pistolic, Jelena; Li, Yuexin; Rehaume, Linda; Hancock, Robert.

In: Journal of Immunology, Vol. 179, No. 11, 01.12.2007, p. 7684-7691.

Research output: Contribution to journalArticle

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AU - Yu, Jie

AU - Mookherjee, Neeloffer

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AU - Rehaume, Linda

AU - Hancock, Robert

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N2 - 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.

AB - 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.

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Yu J, Mookherjee N, Wee K, Bowdish DME, Pistolic J, Li Y et al. Host defense peptide LL-37, in synergy with inflammatory mediator IL-1β, augments immune responses by multiple pathways. Journal of Immunology. 2007 Dec 1;179(11):7684-7691.