Dehdyroepiandrosterone sulfate directly activates protein kinase C-β to increase human neutrophil superoxide generation

Radford, David J., Wang, Keqing, McNelis, Joanne C., Taylor, Angela E., Hechenberger, Georg, Hofmann, Johann, Chahal, Hema, Arlt, Wiebke and Lord, Janet M. (2010). Dehdyroepiandrosterone sulfate directly activates protein kinase C-β to increase human neutrophil superoxide generation. Molecular Endocrinology, 24 (4), pp. 813-821.

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-ß (PKC-ß) in a cell-free assay. Enhanced PKC-ß 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-ß 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.

Publication DOI: https://doi.org/10.1210/me.2009-0390
Divisions: Life & Health Sciences > Biosciences
Aston Medical School
Full Text Link: https://www.ncb ... les/PMC5417533/
Related URLs: http://mend.end ... /4/813.abstract (Publisher URL)
Published Date: 2010-04-01
Authors: Radford, David J.
Wang, Keqing ( 0000-0001-6239-6344)
McNelis, Joanne C.
Taylor, Angela E.
Hechenberger, Georg
Hofmann, Johann
Chahal, Hema
Arlt, Wiebke
Lord, Janet M.

Export / Share Citation


Statistics

Additional statistics for this record