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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 July 24, 2017
Citation Information: J Clin Invest. 2017;127(8):3167-3176. https://doi.org/10.1172/JCI92885.
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Research Article Immunology Inflammation Article has an altmetric score of 80

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

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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 4

Effect of LT synthesis inhibitors in male and female neutrophils and monocytes.

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Effect of LT synthesis inhibitors in male and female neutrophils and mon...
Effects of MK886, licofelone, or Ssi on LTB4 formation in male and female (A and B) neutrophils stimulated at 37°C with LPS (1 μg/ml; 30 minutes) or Ada (0.3 U/ml; 20 minutes) plus fMLP (1 μM; 5 minutes) and (C) monocytes stimulated at 37°C with LPS (1 μg/ml; 15 minutes) plus fMLP (1 μM; 10 minutes). In B, cells were preincubated for 10 minutes with vehicle (0.05% EtOH) or 5α-DHT (10 nM). Data are expressed as percentage of control, mean + SEM; n = 3. *P < 0.05; **P < 0.01; ***P < 0.001 vs. corresponding male (A and C). *P < 0.05; **P < 0.01; ***P < 0.001 for female plus 5α-DHT vs. female plus vehicle, ANOVA plus Bonferroni (B). The amount of LTB4 in 100% controls was as follows: (A) male, 1.0 ± 0.3 ng per 107 cells; female, 2.4 ± 1.0 ng per 107 cells; (B) male, 1.4 ± 0.1 ng per 107 cells (veh) and 1.2 ± 0.2 ng per 107 cells (5α-DHT); female, 3.3 ± 0.5 ng per 107 cells (veh) and 2.1 ± 0.2 ng per 107 cells (5α-DHT); (C) male, 4.8 ± 1.8 ng per 107 cells; female, 11.9 ± 2.7 ng per 107 cells.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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