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Host Defense Peptide LL-37, in Synergy with Inflammatory Mediator IL-1β, Augments Immune Responses by Multiple Pathways¹

Jie Yu^*, Neeloffer Mookherjee^*, Kathleen Wee^*, Dawn M. E. Bowdish, Jelena Pistolic^*, Yuexin Li^*, Linda Rehaume^* and Robert E. W. Hancock^2,*

^* Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada; and Sir William Dunn School of Pathology, University of Oxford, United Kingdom

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-, 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-B was revealed through the demonstration of enhanced phosphorylation of IB and the consequent nuclear translocation of NF-B subunits p50 and p65, as well as the antagonistic effects of an inhibitor of IB 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Genome British Columbia and Genome Prairie for the Pathogenomics of Innate Immunity Research Program and from the Foundation for the National Institutes of Health and Canadian Institutes for Health Research through the Grand Challenges in Global Health Initiative. D.M.E.B. was supported by a Canadian Institute for Health Research Fellowship. R.E.W.H. is the recipient of a Canada Research Chair. K.W. is a recipient of a Translational Research in Infectious Diseases undergraduate co-op studentship.

² Address correspondence and reprint requests to Dr. Robert E. W. Hancock, Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada. E-mail address: bob{at}cmdr.ubc.ca

³ Abbreviations used in this paper: GPCR, G protein-coupled receptor; PK, protein kinase.

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