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Human Cathelicidin Peptide LL-37 Modulates the Effects of IFN- on APCs¹

Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada

The human cathelicidin peptide LL-37 is a multifunctional immunomodulatory and antimicrobial host defense peptide of the human immune system. LL-37 modulates host cell responses to microbial stimuli and also affects the action of other endogenous immune mediators such as IL-1β and GM-CSF. This activity of LL-37 is known to be complex, with the functional outcomes being dependent on the cell type and activation status, timing of exposure, and other immune mediators present. It was demonstrated in this study that LL-37 inhibited cellular responses to IFN-, the key cytokine of Th1-polarized immunity. The inhibitory activity of LL-37 on IFN- responses was characterized in monocytes, macrophages, dendritic cells, and B lymphocytes, showing suppression of cell activation, proliferation, and production of proinflammatory and Th1-polarizing cytokines, and Abs. It was further shown that in monocytes the suppressive effects of LL-37 were mediated through inhibition of STAT1-independent signaling events, involving both the p65 subunit of NF-B and p38 MAPK. This study suggests that LL-37 modulates IFN- responses during both the innate and adaptive phases of immune responses, indicating a new immunomodulatory role for this endogenous peptide. These effects on IFN- activity should be taken into consideration in the development of cathelicidin-based peptides for therapeutic applications as immunomodulatory or microbicidal agents.

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 the Canadian Institutes for Health Research, the Foundation for the National Institutes of Health, and the Bill and Melinda Gates Foundation, through two separate grants from the Grand Challenges in Global Health Initiative. A.N. was supported by postdoctoral fellowships from the Canadian Institutes for Health Research and the Michael Smith Foundation for Health Research. R.E.W.H. is the recipient of a Canada Research Chair.

² This work is dedicated to the memory of our valued colleague Aaron Wyatt, who tragically passed away in a car accident on December 24, 2008.

³ Address correspondence and reprint requests to Dr. Robert E. W. Hancock, Centre for Microbial Diseases and Immunity Research, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, V6T 1Z4, Canada. E-mail address: bob{at}cmdr.ubc.ca

⁴ Abbreviations used in this paper: LTA, lipoteichoic acid; MDP, muramyl dipeptide; NOD-2, nucleotide-binding oligomerization domain-containing 2.

⁵ The online version of this article contains supplemental material.