title: Gender affects macrophage cytokine and prostaglandin E2 production and PGE2 receptor expression after trauma.
abstract: BACKGROUND
  Gender influences morbidity and mortality after injury. Hormonal differences are important; however, the role of prostaglandins as mediators in immune dysfunction relating to gender differences after trauma is unclear. We hypothesized that gender-dependent differences in PGE(2) receptor expression and signaling may be involved in immune-related differences. This study determined prostaglandin receptor subtype (EP1-EP4) expression following injury and determined whether gender differences influence EP receptor expression.
  
  
  METHODS
  BALB/c male and female mice (estrus and pro-estrus) (n = 6 per group) were subjected to femur fracture and 40% hemorrhage (trauma) or sham injury (anesthesia). Seven days later, the splenic macrophages were harvested and stimulated with lipopolysaccharide (Escherichia coli serotype O55:B5). After 6 h mRNA samples were collected for EP receptor mRNA expression and at 24 h supernatants were collected for PGE(2), TNF-alpha, and IL-6 production.
  
  
  RESULTS
  The expression of EP2-4 receptors was higher in female pro-estrus mice compared with male mice. EP1 receptor expression was higher in males than pro-estrus females. There was decreased expression of all four receptors after trauma in female estrus compared with control estrus mice. Macrophage PGE(2), TNF-alpha, and IL-6 production was significantly increased in injured female mice compared with female controls but there were no differences in injured male mice compared with male controls. PGE(2) and TNF-alpha production by traumatized male mice were significantly less than that produced by traumatized pro-estrus females.
  
  
  CONCLUSIONS
  These data suggest gender-related differences in response to traumatic injury and that alterations in specific EP receptor subtypes may be involved in immune dysfunction after injury. Studies to evaluate targeted modulation of these receptor subtypes may provide further insights to gender-specific differences in the immune response after injury.
authors.affiliation: Weill Medical College of Cornell University, Department of Surgery, New York, New York, USA. ppstap@temple.edu
authors.forename: Philip P
authors.initials: PP
authors.lastname: Stapleton
authors.forename: Vivian E Mack
authors.initials: VE
authors.lastname: Strong
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Freeman
authors.forename: Jordan
authors.initials: J
authors.lastname: Winter
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Yan
authors.forename: John M
authors.initials: JM
authors.lastname: Daly
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D015777:Eicosanoids / Q000096:biosynthesis; D004971:Estrus; D005260:Female; D005264:Femoral Fractures / Q000378:metabolism*; D006470:Hemorrhage / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012727:Sex Characteristics; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D015777:Eicosanoids; D015850:Interleukin-6; D020033:Protein Isoforms; C545645:Ptger2 protein, mouse; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone