ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma.
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 5alpha-dihydrotestosterone levels, and addition of 5alpha-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.
Pergola
Carlo
C
Department of Pharmaceutical Analytics, Pharmaceutical Institute, University Tuebingen, 72076 Tuebingen, Germany.
Dodt
Gabriele
G
Rossi
Antonietta
A
Neunhoeffer
Eva
E
Lawrenz
Barbara
B
Northoff
Hinnak
H
Samuelsson
Bengt
B
Rådmark
Olof
O
Sautebin
Lidia
L
Werz
Oliver
O
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001249:Asthma / Q000276:immunology*; D002467:Cell Nucleus; D013196:Dihydrotestosterone / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology
D015289:Leukotrienes; D013196:Dihydrotestosterone; D013739:Testosterone; D001094:Arachidonate 5-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases