Dehdyroepiandrosterone sulfate directly activates protein kinase C-β to increase human neutrophil superoxide generation
Author(s)
Type
Journal Article
Abstract
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in the human circulation and is secreted by the adrenals in an age-dependent fashion, with maximum levels during the third decade and very low levels in old age. DHEAS is considered an inactive metabolite, whereas cleavage of the sulfate group generates dehydroepiandrosterone (DHEA), a crucial sex steroid precursor. However, here we show that DHEAS, but not DHEA, increases superoxide generation in primed human neutrophils in a dose-dependent fashion, thereby impacting on a key bactericidal mechanism. This effect was not prevented by coincubation with androgen and estrogen receptor antagonists but was reversed by the protein kinase C inhibitor Bisindolylmaleimide 1. Moreover, we found that neutrophils are unique among leukocytes in expressing an organic anion-transporting polypeptide D, able to mediate active DHEAS influx transport whereas they did not express steroid sulfatase that activates DHEAS to DHEA. A specific receptor for DHEAS has not yet been identified, but we show that DHEAS directly activated recombinant protein kinase C-β (PKC-β) in a cell-free assay. Enhanced PKC-β activation by DHEAS resulted in increased phosphorylation of p47phox, a crucial component of the active reduced nicotinamide adenine dinucleotide phosphate complex responsible for neutrophil superoxide generation. Our results demonstrate that PKC-β acts as an intracellular receptor for DHEAS in human neutrophils, a signaling mechanism entirely distinct from the role of DHEA as sex steroid precursor and with important implications for immunesenescence, which includes reduced neutrophil superoxide generation in response to pathogens.
Date Issued
2010-04-01
Date Acceptance
2010-01-07
Citation
Molecular Endocrinology, 2010, 24 (4), pp.813-821
ISSN
0888-8809
Publisher
Endocrine Society
Start Page
813
End Page
821
Journal / Book Title
Molecular Endocrinology
Volume
24
Issue
4
Copyright Statement
Copyright © 2010 by The Endocrine Society.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/20172962
PII: me.2009-0390
Subjects
AGE
CELL DIFFERENTIATION
CHOLESTEROL SULFATE
DEHYDROEPIANDROSTERONE DHEA
Endocrinology & Metabolism
EXPRESSION
IDENTIFICATION
Life Sciences & Biomedicine
REPLACEMENT
RESISTANCE
Science & Technology
SERUM DEHYDROEPIANDROSTERONE
VACCINATION
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2010-02-19