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

C Pergola, G Dodt, A Rossi… - Proceedings of the …, 2008 - National Acad Sciences
C Pergola, G Dodt, A Rossi, E Neunhoeffer, B Lawrenz, H Northoff, B Samuelsson…
Proceedings of the National Academy of Sciences, 2008National Acad Sciences
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 (eg, 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 …
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.
National Acad Sciences