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PNAS 105 (50): 19881-19886

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

ERK-mediated regulation of leukotriene biosynthesis by androgens: A molecular basis for gender differences in inflammation and asthma

Carlo Pergolaa,b, Gabriele Dodtc, Antonietta Rossib, Eva Neunhoefferd, Barbara Lawrenzd, Hinnak Northoffe, Bengt Samuelssonf,1, Olof Rådmarkf, Lidia Sautebinb, and Oliver Werza,1

aDepartment of Pharmaceutical Analytics, Pharmaceutical Institute; cInterfakultäres Institut für Biochemie; dUniversity Women's Hospital; and eInstitute for Clinical and Experimental Transfusion Medicine, University Medical Center Tuebingen, University Tuebingen, 72076 Tuebingen, Germany; bDepartment of Experimental Pharmacology, University of Naples Federico II, 80131 Naples, Italy; and fDepartment of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, S-17177 Stockholm, Sweden

Contributed by Bengt Samuelsson, October 10, 2008

Received for publication August 27, 2008.

Abstract: 5-Lipoxygenase initiates the biosynthesis of leukotrienes, lipid mediators involved in normal host defense and in inflammatory and allergic disorders. Despite an obvious gender bias in leukotriene-related diseases (e.g., asthma), gender aspects have been neglected in studies on leukotrienes and 5-lipoxygenase. Here, we show that leukotriene formation in stimulated whole blood or neutrophils from males is substantially lower compared with females, accompanied by changed 5-lipoxygenase trafficking. This is due to gender-specific differential activation of extracellular signal-regulated kinases (ERKs). The differences are directly related to variant male/female testosterone plus 5{alpha}-dihydrotestosterone levels, and addition of 5{alpha}-dihydrotestosterone to female blood or neutrophils reduced the high (female) LT biosynthesis capacity to low (male) levels. In conclusion, regulation of ERKs and leukotriene formation by androgens constitutes a molecular basis for gender differences in the inflammatory response, and in inflammatory diseases such as asthma.

Key Words: 5-lipoxygenase • arachidonic acid

Freely available online through the PNAS open access option.

Author contributions: C.P., B.L., H.N., B.S., O.R., L.S., and O.W. designed research; C.P., G.D., A.R., and E.N. performed research; C.P., G.D., A.R., L.S., and O.W. analyzed data; and C.P. and O.W. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0809120105/DCSupplemental.

1To whom correspondence may be addressed. E-mail: bengt.samuelsson{at}ki.se or oliver.werz{at}uni-tuebingen.de

© 2008 by The National Academy of Sciences of the USA

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