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Sexual dimorphism in superantigen shock involves elevated TNF-alpha and TNF-alpha-induced hepatic apoptosis

Faulkner, L; Altmann, DM; Ellmerich, S; Huhtaniemi, I; Stamp, G; Sriskandan, S; (2007) Sexual dimorphism in superantigen shock involves elevated TNF-alpha and TNF-alpha-induced hepatic apoptosis. AM J RESP CRIT CARE , 176 (5) 473 - 482. 10.1164/rccm.200611-1712OC.

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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-a. 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.

Type: Article
Title: Sexual dimorphism in superantigen shock involves elevated TNF-alpha and TNF-alpha-induced hepatic apoptosis
DOI: 10.1164/rccm.200611-1712OC
Keywords: superantigen, sepsis, tumor necrosis factor-alpha, apoptosis, TUMOR-NECROSIS-FACTOR, STAPHYLOCOCCAL-ENTEROTOXIN-B, DQ TRANSGENIC MICE, GENDER-DIFFERENCES, LIVER-INJURY, GENE-EXPRESSION, FEMALE MICE, IN-VIVO, T-CELL, STREPTOCOCCUS-PYOGENES
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/369209
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