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Published online before print January 11, 2008

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(Journal of Leukocyte Biology. 2008;83:998-1008.)
© 2008 by Society for Leukocyte Biology

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

Arya Biragyn^*,1, 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

¹ Correspondence: Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Box 21, Baltimore, MD 21224, USA. E-mail: biragyna{at}mail.nih.gov

Mammalian antimicrobial peptides, including β-defensins, represent an ancient arm of innate immunity designed to directly neutralize invading microbes. Previously, we demonstrated that murine β-defensin 2 (mDF2β) 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 mDF2β 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 β-defenisn 3 was also able to activate and kill DCs. We propose that β-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