Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males
Simona Pace, … , Lidia Sautebin, Oliver Werz
Simona Pace, … , Lidia Sautebin, Oliver Werz
Published August 1, 2017; First published July 24, 2017
Citation Information: J Clin Invest. 2017;127(8):3167-3176. https://doi.org/10.1172/JCI92885.
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Categories: Research Article Immunology Inflammation

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Abstract

Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO–activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor–induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.

Authors

Simona Pace, Carlo Pergola, Friederike Dehm, Antonietta Rossi, Jana Gerstmeier, Fabiana Troisi, Helmut Pein, Anja M. Schaible, Christina Weinigel, Silke Rummler, Hinnak Northoff, Stefan Laufer, Thorsten J. Maier, Olof Rådmark, Bengt Samuelsson, Andreas Koeberle, Lidia Sautebin, Oliver Werz

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Figure 5

5-LO/FLAP complex assembly is sex dependent and blocked by 5α-DHT.

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5-LO/FLAP complex assembly is sex dependent and blocked by 5α-DHT. (A) H...
(A) Human male and female neutrophils or monocytes were stimulated at 37°C with 2.5 μM A23187 or left untreated (w/o) for 15 minutes. (B) Female neutrophils or monocytes were preincubated at RT for 10 minutes with 10 nM 5α-DHT, 100 nM MK886, or vehicle (0.1% DMSO) and then stimulated with 2.5 μM A23187 or left untreated for 20 minutes. (C) PMs from male and female mice were preincubated at 37°C for 10 minutes with 10 nM 5α-DHT or vehicle (0.1% DMSO) and then stimulated with 2.5 μM A23187 or left untreated for 20 minutes. Then, in situ PLA, using proximity probes against mouse anti–5-LO and rabbit anti-FLAP, was performed. DAPI (blue) was used to stain the nucleus, and in situ PLA signals (magenta dots) visualized 5-LO/FLAP interaction. Scale bars: 5 μm (insets); 25 μm (overview). Results are representative of approximately 100 individual cells of n = 3 independent experiments.