Leukotrienes are lipid mediators that are produced by enzymes called lipoxygenases and are involved in chronic inflammatory diseases, such as asthma. One factor that regulates the activity of 5-lipoxygenase (5-LO) is its subcellular localization. In resting cells, 5-LO is found in the cytosol or inside the nucleus; in cells exposed to inflammatory or Ca2+-releasing stimuli, 5-LO moves to the nuclear envelope, where proteins that assist in leukotriene biosynthesis are located. Pergola et al. showed that more leukotriene B4 and other 5-LO products were produced in stimulated blood and neutrophils (the primary source of 5-LO products in the blood) from women compared with those from men. Gender differences in 5-LO activity were caused by differential subcellular localization. In neutrophils from females, 5-LO was located primarily in the cytoplasm in unstimulated cells and at the nuclear envelope in stimulated cells. In contrast, 5-LO in neutrophils from males displayed a cytoplasmic and nucleoplasmic distribution, which was not altered by stimulation. 5-LO rapidly translocated to the nuclear compartment in 5α-dihydrotestosterone (5α-DHT)–treated neutrophils from females, whereas 17β-estradiol and progesterone had no effect on 5-LO distribution in neutrophils from either females or males. More important, treatment of blood or neutrophils from females with 5α-DHT, but not with female sex hormones, suppressed 5-LO activity. In addition to subcellular localization, 5-LO activity is affected by phosphorylation by several kinases, including extracellular signal–regulated kinase 2 (ERK2). Treatment with ERK2 inhibitors caused the pre- and poststimulation distribution of 5-LO in neutrophils from males to resemble that in neutrophils from females and also blocked the 5α-DHT–induced redistribution of 5-LO to the nuclear compartment in neutrophils from females. As would be predicted, neutrophils from males displayed higher ERK2 activity, as measured by phosphorylation of the kinase and one of its substrates, Elk-1. The authors speculate that their data may help to explain some gender-related clinical findings, such as the higher incidence of severe asthma in female patients.
C. Pergola, G. Dodt, A. Rossi, E. Neunhoeffer, B. Lawrenz, H. Northoff, B. Samuelsson, O. Rådmark, L. Sautebin, O. Werz, ERK-mediated regulation of leukotriene biosynthesis by androgens: A molecular basis for gender differences in inflammation and asthma. Proc. Natl. Acad. Sci. U.S.A. 105, 19881–19886 (2008). [Abstract] [Full Text]