title: ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma.
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 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.
authors.affiliation: Department of Pharmaceutical Analytics, Pharmaceutical Institute, University Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dodt
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Eva
authors.initials: E
authors.lastname: Neunhoeffer
authors.forename: Barbara
authors.initials: B
authors.lastname: Lawrenz
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Bengt
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Olof
authors.initials: O
authors.lastname: Rådmark
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: 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
chemical_list: D015289:Leukotrienes; D013196:Dihydrotestosterone; D013739:Testosterone; D001094:Arachidonate 5-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases