Early gene expression changes induced by the bacterial superantigen staphylococcal enterotoxin B and its modulation by a proteasome inhibitor

Govindarajan Rajagopalan, Ashenafi Y. Tilahun, Yan W. Asmann, Chella S. David

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Toxic shock syndrome (TSS) is an acute, serious systemic illness caused by bacterial superantigens. Nonavailability of a suitable animal model until recently has hampered an in-depth understanding of the pathogenesis of TSS. In the current study, we characterized the early molecular events underlying TSS using our HLA-DR3 transgenic mouse model. Gene expression profiling using DNA microarrays identified a rapid and significant upregulation of several pro- as well as anti-inflammatory mediators, many of which have never been previously described in TSS. In vivo administration of staphylococcal enterotoxin B (SEB) led to an increase in the expression of Th0- (IL-2, 240-fold); Th1-(IFN-γ, 360-fold; IL-12, 8-fold); Th2- (IL-4, 53-fold; IL-5, 4-fold) as well as Th17-type cytokines (IL-21, 19-fold; IL-17, 5-fold). The immunoregulatory cytokines (IL-6, 700-fold; IL-10, 18-fold); CC chemokines (such as CCL 2, 11, 3, 24, 17, 12, 7), CXC chemokines (such as CXCL 1, 2, 5, 11, 10, 19); and several proteases (matrix metalloproteinases 13, 8, 3, and 9) were also upregulated. Serum levels of several of these cytokines/chemokines were also significantly elevated. Pathway analyses revealed significant modulation in a variety of biochemical and cellular functions, providing molecular insights into the pathogenesis of TSS. Administration of bortezomib, a clinically approved proteasome inhibitor capable of blocking NF-κB pathway, was able to significantly modulate the expression of a variety of genes induced by SEB. Thus, our study showed that TSS is a complex process and emphasized the potential of use of bortezomib in the therapy of superantigen-induced TSS.

Original languageEnglish (US)
Pages (from-to)279-293
Number of pages15
JournalPhysiological Genomics
Volume37
Issue number3
DOIs
StatePublished - May 2009

Keywords

  • Cytokines
  • HLA class II transgenic mice
  • Microarray
  • Rodents
  • T cell response
  • Toxic shock

ASJC Scopus subject areas

  • Physiology
  • Genetics

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