It is well known that women are at a much higher risk of developing many autoimmune disorders. Why the disparity? A study released in this week’s Proceedings of the National Academy of Sciences has identified a molecular gender difference, regulated by androgens, which appears to be involved in a signaling cascade regulating leukotriene biosynthesis. This may provide a molecular basis for the gender difference seen in the inflammatory response and autoimmune diseases, and an important target in developing extracellular signal-regulated kinases (ERKs) to reduce autoimmunity.
These findings demonstrate possible treatment approaches to autoimmunity. It may be possible to develop medications to target this pathway, or perhaps, new techniques that could expose female neutrophils to androgen containing male plasma.
From the study:
Despite a known gender bias in diseases such as asthma, the influence of gender at the molecular level has not been studied. 5-Lipoxygenase initiates the biosynthesis of leukotrienes-lipid mediators involved in normal host defense and in inflammatory and allergic disorders. Carlo Pergola et al. found that androgens down-regulate leukotriene synthesis by altering 5-lipoxygenase trafficking in neutrophils. The authors report that the enzyme catalyzes the formation of leukotrienes from arachidonic acid in neutrophils by incorporating molecular oxygen into the essential fatty acid. The rate of leukotriene synthesis depends, in part, on the location of 5-lipoxygenase within the neutrophil. Increasing levels of testosterone (or 5a-dihydrotestosterone) activates a signaling cascade that causes the lipoxygenase to move from the cytoplasm of the neutrophil to the perinuclear region. Pergola et al. report that the addition of 5a-dihydrotestosterone to female blood or neutrophils reduced the high (female) leukotriene biosynthesis capacity to low (male) levels. The authors suggest that regulation of leukotriene biosynthesis by androgens may provide a molecular basis for the gender difference seen in the inflammatory response and in inflammation-mediated diseases.
PNAS abstract: ERK-mediated regulation of leukotriene biosynthesis by androgens: A molecular basis for gender differences in inflammation and asthma PNAS, December 16, 2008, vol. 105 no. 50 19881-19886
