Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Immunology Inflammation

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

  • Text
  • PDF
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

×

Figure 1

Sex differences in the production of LTB4 and in the potency of LT biosynthesis inhibitors in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Sex differences in the production of LTB4 and in the potency of LT biosy...
(A) LTB4 levels in the thoracic cavity 2 hours after λ-carrageenan injection in male and female rats. n = 35 (5 rats/sex in 7 experiments); unpaired 2-tailed t test. Data passed normality test. ***P < 0.001. (B) Effects of zileuton and MK886 on pleural LTB4 levels in male and female rats 2 hours after λ-carrageenan injection. Vehicle or compounds were injected i.p. 30 minutes prior to λ-carrageenan. Data show percentage of controls, mean + SEM. For 10 mg/kg zileuton and 0.5 mg/kg MK886, n = 10 (5 rats/sex in 2 experiments); for the other doses, n = 5 (5 rats/sex in 1 experiment). The different doses were tested in independent experiments performed side by side with male/female rats and controls. *P < 0.05; **P < 0.01 vs. corresponding males, ANOVA plus Bonferroni. (C) LTB4 levels in the peritoneal cavity 15 minutes after i.p. zymosan injection in male and female mice. n = 5 (5 mice/sex in 1 experiment); unpaired 2-tailed t test. (D) Mice received 1 mg/kg MK886 or 0.5 mg/kg 5α-DHT or vehicle 30 minutes prior to zymosan injection. LTB4 levels in the peritoneal cavity of male and female mice were assessed 15 minutes after i.p. zymosan. n = 5 (5 mice/sex in 1 experiment); ANOVA plus Bonferroni. (E) Plasma levels of MK886 after i.p. injection of 1 mg/kg in male and female mice at 0, 30, 60, and 240 minutes after administration. n = 3 (3 mice/sex in 1 experiment); no significant differences, ANOVA plus Bonferroni.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts