title: In vivo sex differences in leukotriene biosynthesis in zymosan-induced peritonitis.
abstract: Leukotrienes (LTs) are 5-lipoxygenase (5-LO) metabolites which are implicated in sex-dependent inflammatory diseases (asthma, autoimmune diseases, etc.). We have recently reported sex differences in LT biosynthesis in in vitro models such as human whole blood, neutrophils and monocytes, due to down-regulation of 5-LO product formation by androgens. Here we present evidences for sex differences in LT synthesis and related inflammatory reactions in an in vivo model of inflammation (mouse zymosan-induced peritonitis). On the cellular level, differential 5-LO subcellular compartmentalization in peritoneal macrophages (PM) from male and female mice might be the basis for these differences. Sex differences in vascular permeability and neutrophil recruitment (cell number and myeloperoxidase activity) into peritoneal cavity were evident upon intraperitoneal zymosan injection, with more prominent responses in female mice. This was accompanied by higher levels of LTC4 and LTB4 in peritoneal exudates of female compared to male mice. Interestingly, LT peritoneal levels in orchidectomized mice were higher than in sham male mice. In accordance with the in vivo results, LT formation in stimulated PM from female mice was higher than in male PM, accompanied by alterations in 5-LO subcellular localization. The increased formation of LTC4 in incubations of PM from orchidectomized mice confirms a role of sex hormones. In conclusion, sex differences observed in LT biosynthesis during peritonitis in vivo may be related, at least in part, to a variant 5-LO localization in PM from male and female mice.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy. Electronic address: antrossi@unina.it.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Friedrich-Schiller-University, Jena, Germany. Electronic address: carlo.pergola@uni-jena.de.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy. Electronic address: simona.pace@unina.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Pace
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Electronic address: olof.radmark@ki.se.
authors.forename: Olof
authors.initials: O
authors.lastname: Rådmark
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Friedrich-Schiller-University, Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy. Electronic address: sautebin@unina.it.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001202:Ascitic Fluid / Q000166:cytology / Q000378:metabolism; D002199:Capillary Permeability; D005260:Female; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000378:metabolism*; D017997:Leukotriene C4 / Q000096:biosynthesis / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009919:Orchiectomy; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D012727:Sex Characteristics; D013739:Testosterone / Q000097:blood; D015054:Zymosan
chemical_list: D007975:Leukotriene B4; D017997:Leukotriene C4; D013739:Testosterone; D015054:Zymosan; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase
keywords: Leukotriene B(4) (PubMed CID: 5280492); Leukotriene C(4) (PubMed CID: 5283121); Leukotrienes; Peritonitis; Sex differences; Zymosan; Zymosan (PubMed CID: 11375554)