title: Sexual dimorphism in superantigen shock involves elevated TNF-alpha and TNF-alpha induced hepatic apoptosis.
abstract: BACKGROUND
  There is conflicting evidence regarding sex differences in the outcome from severe sepsis and toxic shock. Superantigen-mediated toxic shock affects a higher proportion of female patients.
  
  
  OBJECTIVE
  The objective of the current study was to investigate sexual dimorphism in superantigen-associated sepsis and in superantigen-mediated shock and to identify the key mechanisms responsible for this sex difference.
  
  
  METHODS
  We measured mortality and serum cytokines after induction of sepsis with isogenic superantigen-positive and superantigen-negative Streptococcus pyogenes in HLA class II transgenics. During superantigen-mediated toxic shock, we measured mortality, T-cell responses, systemic tumor necrosis factor (TNF)-alpha and TNF receptors, TNF-alpha-induced hepatocyte apoptosis, and conditioning of these responses by tamoxifen treatment.
  
  
  RESULTS
  In both superantigen-associated sepsis and in superantigen-mediated shock, serum TNF-alpha was increased in females compared with males. This was not attributable to a detectable difference in splenic TNF-alpha transcription; rather, serum soluble TNF receptors were higher in males. Pretreatment of females with the estrogen receptor modulator tamoxifen increased serum soluble TNF receptors, reduced the early serum TNF-alpha response, and improved mortality in females challenged with staphylococcal enterotoxin B. Lethal superantigen shock was characterized by hepatocyte apoptosis, and was reproduced by injection of TNF-alpha. Females had enhanced susceptibility to TNF-alpha-mediated lethality. TNF-alpha-induced hepatocyte apoptosis was greater in females, and was reduced by tamoxifen pretreatment.
  
  
  CONCLUSIONS
  Sexual dimorphism in experimental superantigen toxic shock results from increased systemic TNF-alpha in females, coupled with an increased susceptibility to TNF-alpha-induced hepatocyte apoptosis. Both processes are abrogated by estrogen receptor modulators.
authors.affiliation: Department of Infectious Diseases and Immunity, Imperial College, London, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Faulkner
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Ellmerich
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Shiranee
authors.initials: S
authors.lastname: Sriskandan
mesh_terms: D000818:Animals; D017209:Apoptosis; D004198:Disease Susceptibility; D005260:Female; D006683:HLA-DQ Antigens; D015798:HLA-DR1 Antigen; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018805:Sepsis / Q000276:immunology* / Q000503:physiopathology; D012727:Sex Characteristics; D012772:Shock, Septic / Q000276:immunology / Q000503:physiopathology; D018089:Superantigens / Q000276:immunology* / Q000494:pharmacology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015798:HLA-DR1 Antigen; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha