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Sexual Dimorphism in Superantigen Shock Involves Elevated TNF- and TNF-–induced Hepatic Apoptosis

Departments of ¹ Infectious Diseases and Immunity, ² Reproductive Biology, and ³ Histopathology, Imperial College, London, United Kingdom

Correspondence and requests for reprints should be addressed to Shiranee Sriskandan, F.R.C.P., Ph.D., Department of Infectious Diseases and Immunity, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail: s.sriskandan{at}imperial.ac.uk

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)- and TNF receptors, TNF-–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- was increased in females compared with males. This was not attributable to a detectable difference in splenic TNF- 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- 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-. Females had enhanced susceptibility to TNF-–mediated lethality. TNF-–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- in females, coupled with an increased susceptibility to TNF-–induced hepatocyte apoptosis. Both processes are abrogated by estrogen receptor modulators.

Key Words: superantigen • sepsis • tumor necrosis factor- • apoptosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Females appear to be more susceptible to shock or death in the specific setting of severe sepsis and superantigen-mediated toxic shock. What This Study Adds to the Field Sexual dimorphism in toxic shock results from an early and enhanced presence of TNF- in females, coupled with an increased susceptibility to TNF-–-induced hepatocyte apoptosis, both of which are dependent on estrogen receptor signaling.

 

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