Cyclooxygenase 2 pathway and its therapeutic inhibition in superantigen-induced toxic shock

Govindarajan Rajagopalan, Yan W. Asmann, Anna K. Lytle, Ashenafi Y. Tilahun, Jayne E. Theuer, Michele K. Smart, Robin Patel, Chella S. David

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Bacterial superantigens are a family of exotoxins that are the most potent T-cell activators known. Because of their ability to induce strong immune activation, superantigens have been implicated in a variety of diseases ranging from self-limiting food poisoning to more severe toxic shock syndrome (TSS) and have the potential to be used as agents of bioterrorism. Nonetheless, the precise molecular mechanisms by which T-cell activation by superantigens lead to acute systemic inflammatory response, multiple organ dysfunction, and ultimately death are unclear. Inadequate understanding of the pathogenesis has resulted in lack of development of effective therapy for superantigen-induced TSS. To fill these deficiencies, we systematically dissected the molecular pathogenesis of superantigen-induced TSS using the humanized human leukocyte antigen-DR3 transgenic mouse model by microarray-based gene expression profiling. Splenic expression of prostaglandin-endoperoxide synthase 2 (PTGS-2; also called cyclooxygenase 2 or COX-2) gene was increased by several hundred folds shortly after systemic superantigen (staphylococcal enterotoxin B [SEB]) exposure. In addition, expressions of several genes associated with eicosanoid pathway were significantly modulated by SEB, as analyzed by dedicated software. Given the importance of the COX-2 pathway in inflammation, we examined whether therapeutic inhibition of COX-2 by a highly selective inhibitor, CAY10404, could be beneficial. Our studies showed that i.p. administration of CAY10404 (50 mg/kg) immediately after challenge with 10 ng of SEB was unable to inhibit SEB-induced in vivo cytokine/chemokine production or T-cell activation/ proliferation and did not prevent superantigen-associated thymocyte apoptosis.

Original languageEnglish (US)
Pages (from-to)721-728
Number of pages8
JournalShock
Volume30
Issue number6
DOIs
StatePublished - Dec 1 2008

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Keywords

  • Cytokines
  • Rodents
  • T-cell response
  • Toxic shock

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Rajagopalan, G., Asmann, Y. W., Lytle, A. K., Tilahun, A. Y., Theuer, J. E., Smart, M. K., Patel, R., & David, C. S. (2008). Cyclooxygenase 2 pathway and its therapeutic inhibition in superantigen-induced toxic shock. Shock, 30(6), 721-728. https://doi.org/10.1097/SHK.0b013e31817048f7