ERK-mediated regulation of leukotriene biosynthesis by androgens: A molecular basis for gender differences in inflammation and asthma
Open Access
- 16 December 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 105 (50), 19881-19886
- https://doi.org/10.1073/pnas.0809120105
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 5α-dihydrotestosterone levels, and addition of 5α-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.Keywords
This publication has 32 references indexed in Scilit:
- Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after Klebsiella pneumoniae infectionRespiratory Research, 2008
- Impact of gender on asthma in childhood and adolescence: a GA2LEN reviewAllergy, 2007
- LeukotrienesNew England Journal of Medicine, 2007
- 5-Lipoxygenase: regulation of expression and enzyme activityTrends in Biochemical Sciences, 2007
- Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4productionProceedings of the National Academy of Sciences, 2006
- Therapeutic implications of sex differences in asthma and atopyArchives of Disease in Childhood, 2003
- Extracellular signal‐regulated kinases phosphorylate 5lipoxygenase and stimulate 5‐lipoxygenase product formation in leukocytesThe FASEB Journal, 2002
- Colocalization of Cytosolic Phospholipase A2, 5‐Lipoxygenase, and 5‐Lipoxygenase‐Activating Protein at the Nuclear Membrane of A23187‐Stimulated Human NeutrophilsEuropean Journal of Biochemistry, 1996
- Lipopolysaccharides prime whole human blood and isolated neutrophils for the increased synthesis of 5-lipoxygenase products by enhancing arachidonic acid availability: involvement of the CD14 antigen.The Journal of Experimental Medicine, 1993
- Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and InflammationScience, 1983