Cyclooxygenase 2 pathway and its therapeutic inhibition in superantigen-induced toxic shock.
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 microg 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.
Rajagopalan
Govindarajan
G
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. rajagopalan.govindarajan@mayo.edu
Asmann
Yan W
YW
Lytle
Anna K
AK
Tilahun
Ashenafi Y
AY
Theuer
Jayne E
JE
Smart
Michele K
MK
Patel
Robin
R
David
Chella S
CS
D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism* / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012772:Shock, Septic / Q000139:chemically induced* / Q000235:genetics / Q000517:prevention & control*; D013450:Sulfones / Q000494:pharmacology; D018089:Superantigens / Q000494:pharmacology*
C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D004768:Enterotoxins; D007555:Isoxazoles; D013450:Sulfones; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D051546:Cyclooxygenase 2