Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 105 (50): 19881-19886

Copyright © 2008 by the National Academy of 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

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

© 2008 by The National Academy of Sciences of the USA

Indirubin-3'-monoxime exerts a dual mode of inhibition towards leukotriene-mediated vascular smooth muscle cell migration.
T. Blazevic, A. M. Schaible, K. Weinhaupl, D. Schachner, F. Nikels, C. Weinigel, D. Barz, A. G. Atanasov, C. Pergola, O. Werz, et al. (2014)
Cardiovasc Res 101, 522-532
   Abstract »    Full Text »    PDF »
Reconstitution of anti-allergic activities of PG102 derived from Actinidia arguta by combining synthetic chemical compounds.
D. Kim, J. Choi, M.-J. Kim, S. H. Kim, S. H. Cho, and S. Kim (2013)
Experimental Biology and Medicine 238, 631-640
   Abstract »    Full Text »    PDF »
Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663.
N. C. Gilbert, Z. Rui, D. B. Neau, M. T. Waight, S. G. Bartlett, W. E. Boeglin, A. R. Brash, and M. E. Newcomer (2012)
FASEB J 26, 3222-3229
   Abstract »    Full Text »    PDF »
Testosterone suppresses phospholipase D, causing sex differences in leukotriene biosynthesis in human monocytes.
C. Pergola, A. Rogge, G. Dodt, H. Northoff, C. Weinigel, D. Barz, O. Radmark, L. Sautebin, and O. Werz (2011)
FASEB J 25, 3377-3387
   Abstract »    Full Text »    PDF »
Cinnamyl-3,4-Dihydroxy-{alpha}-Cyanocinnamate Is a Potent Inhibitor of 5-Lipoxygenase.
C. Pergola, B. Jazzar, A. Rossi, U. Buehring, S. Luderer, F. Dehm, H. Northoff, L. Sautebin, and O. Werz (2011)
J. Pharmacol. Exp. Ther. 338, 205-213
   Abstract »    Full Text »    PDF »
HNE-induced 5-LO expression is regulated by NF-{kappa}B/ERK and Sp1/p38 MAPK pathways via EGF receptor in murine macrophages.
S. J. Lee, C. E. Kim, K. W. Seo, and C. D. Kim (2010)
Cardiovasc Res 88, 352-359
   Abstract »    Full Text »    PDF »
The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease.
D. Poeckel and C. D. Funk (2010)
Cardiovasc Res 86, 243-253
   Abstract »    Full Text »    PDF »
Sex-Specific Association of Depression and a Haplotype in Leukotriene A4 Hydrolase Gene.
J. Zhao, A. A. Quyyumi, R. Patel, A. M. Zafari, E. Veledar, S. Onufrak, L. H. Shallenberger, L. Jones, and V. Vaccarino (2009)
Psychosom Med 71, 691-696
   Abstract »    Full Text »    PDF »
Dual 12/15- and 5-Lipoxygenase Deficiency in Macrophages Alters Arachidonic Acid Metabolism and Attenuates Peritonitis and Atherosclerosis in ApoE Knock-out Mice.
D. Poeckel, K. A. Zemski Berry, R. C. Murphy, and C. D. Funk (2009)
J. Biol. Chem. 284, 21077-21089
   Abstract »    Full Text »    PDF »
5-Lipoxygenase: mechanisms of regulation.
O. Radmark and B. Samuelsson (2009)
J. Lipid Res. 50, S40-S45
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882