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Published online before print January 11, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1007700

Received for publication October 19, 2007.
Revised December 5, 2007.
Accepted for publication December 13, 2007.

Article

Murine -defensin 2 promotes TLR-4/MyD88-mediated and NF-B-dependent atypical death of APCs via activation of TNFR2

Arya Biragyn ^*@, Marta Coscia , Kunio Nagashima , Michael Sanford , Howard A. Young , and Purevdorj Olkhanud ^*

*Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA; Science Applications International Corporation-Frederick, Inc., Frederick, Maryland, USA; Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, USA; and Divisione di Ematologia dell’Universita’ di Torino, Laboratorio di Ematologia Oncologica, CeRMS, Azienda Ospedaliera San Giovanni Battista, Torino, Italy

^@ To whom correspondence should be addressed. E-mail: biragyna{at} mail.nih.gov.

	Abstract

Mammalian antimicrobial peptides, including -defensins, represent an ancient arm of innate immunity designed to directly neutralize invading microbes. Previously, we demonstrated that murine -defensin 2 (mDF2) also acted as an endogenous ligand for TLR-4-activating maturation of dendritic cells (DCs). Herein, we report that this TLR-4 –dependent activation leads to induction of an atypical cell death that is unexpectedly exaggerated by the inhibition of caspases. Experiments using APCs with nonfunctional TNF- or its receptors suggest that this is a NF-B- and TNF--dependent process that does not require TNFR1. We demonstrate that mDF2 triggers a TNFR2-mediated signaling cascade of "self-destruction" through up-regulation of membrane-bound TNF- and TNFR2. This appears not to be an isolated phenomenon, as human synthetic -defenisn 3 was also able to activate and kill DCs. We propose that -defenins may play an important immunoregulatory role as controllers of the natural process of elimination of activated APCs.

Key Words: antimicrobial peptide • DC maturation • immunomodulation

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