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  • Title: Sexual dimorphism in superantigen shock involves elevated TNF-alpha and TNF-alpha induced hepatic apoptosis.
    Author: Faulkner L, Altmann DM, Ellmerich S, Huhtaniemi I, Stamp G, Sriskandan S.
    Journal: Am J Respir Crit Care Med; 2007 Sep 01; 176(5):473-82. PubMed ID: 17575097.
    Abstract:
    RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
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