Journal article
Macrocyclic θ-defensins suppress tumor necrosis factor-α (TNF-α) shedding by inhibition of TNF-α–converting enzyme
The Journal of biological chemistry, Vol.293(8), pp.2725-2734
02/23/2018
DOI: 10.1074/jbc.RA117.000793
PMCID: PMC5827436
PMID: 29317500
Abstract
Theta-defensins (θ-defensins) are macrocyclic peptides expressed exclusively in granulocytes and selected epithelia of Old World monkeys. They contribute to anti-pathogen host defense responses by directly killing a diverse range of microbes. Of note, θ-defensins also modulate microbe-induced inflammation by affecting the production of soluble tumor necrosis factor (sTNF) and other proinflammatory cytokines. Here, we report that natural rhesus macaque θ-defensin (RTD) isoforms regulate sTNF cellular release by inhibiting TNF-α–converting enzyme (TACE; also known as adisintegrin and metalloprotease 17; ADAM17), the primary pro-TNF sheddase. Dose-dependent inhibition of cellular TACE activity by RTDs occurred when leukocytes were stimulated with live Escherichia coli cells as well as numerous Toll-like receptor agonists. Moreover, the relative inhibitory potencies of the RTD isoforms strongly correlated with their suppression of TNF release by stimulated blood leukocytes and THP-1 monocytes. RTD isoforms also inhibited ADAM10, a sheddase closely related to TACE. TACE inhibition was abrogated by introducing a single opening in the RTD-1 backbone, demonstrating that the intact macrocycle is required for enzyme inhibition. Enzymologic analyses showed that RTD-1 is a fast binding, reversible, non-competitive inhibitor of TACE. We conclude that θ-defensin–mediated inhibition of pro-TNF proteolysis by TACE represents a rapid mechanism for the regulation of sTNF and TNF-dependent inflammatory pathways. Molecules with structural and functional features mimicking those of θ-defensins may have clinical utility as TACE inhibitors for managing TNF-driven diseases.
Details
- Title: Subtitle
- Macrocyclic θ-defensins suppress tumor necrosis factor-α (TNF-α) shedding by inhibition of TNF-α–converting enzyme
- Creators
- Justin B Schaal - Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089Thorsten Maretzky - Hospital for Special Surgery, Weill Cornell Medicine, New York, New York 10021Dat Q Tran - Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089Patti A Tran - Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089Prasad Tongaonkar - Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089Carl P Blobel - Hospital for Special Surgery, Weill Cornell Medicine, New York, New York 10021André J Ouellette - Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089Michael E Selsted - Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(8), pp.2725-2734
- DOI
- 10.1074/jbc.RA117.000793
- PMID
- 29317500
- PMCID
- PMC5827436
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- AR068833; AI22931; DE021341; GM64750 / National Institutes of Health 5997 / Arthritis Foundation
- Language
- English
- Date published
- 02/23/2018
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984094398202771
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