Murine beta-defensin 2 promotes TLR-4/MyD88-mediated and NF-kappaB-dependent atypical death of APCs via activation of TNFR2.
Mammalian antimicrobial peptides, including beta-defensins, represent an ancient arm of innate immunity designed to directly neutralize invading microbes. Previously, we demonstrated that murine beta-defensin 2 (mDF2beta) 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-alpha or its receptors suggest that this is a NF-kappaB- and TNF-alpha-dependent process that does not require TNFR1. We demonstrate that mDF2beta triggers a TNFR2-mediated signaling cascade of "self-destruction" through up-regulation of membrane-bound TNF-alpha and TNFR2. This appears not to be an isolated phenomenon, as human synthetic beta-defenisn 3 was also able to activate and kill DCs. We propose that beta-defenins may play an important immunoregulatory role as controllers of the natural process of elimination of activated APCs.
Biragyn
Arya
A
Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. biragyna@mail.nih.gov
Coscia
Marta
M
Nagashima
Kunio
K
Sanford
Michael
M
Young
Howard A
HA
Olkhanud
Purevdorj
P
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology* / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D016923:Cell Death / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D023083:beta-Defensins / Q000494:pharmacology*
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D047889:Receptors, Tumor Necrosis Factor, Type II; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D023083:beta-Defensins