Transcriptional activation of IL-1 beta and tumor necrosis factor-alpha genes by MHC class II ligands

Abstract

Ligands that bind MHC class II (Ia) molecules, including staphylococcal exotoxins (SE) and mAb induce IL-1 and TNF secretion in human monocytes and monocytic cell lines. In this study, we have analyzed the mechanisms by which SE induce IL-1 beta and TNF-alpha production. Treatment of human peripheral blood monocytes with staphylococcal exotoxin B and toxic shock syndrome toxin-1 resulted in a biphasic increase of IL-1 beta mRNA that lasted more than 12 h and in a more transient rise in TNF-alpha mRNA. A F(ab) preparation of the anti-HLA DR mAb L243 also caused a significant increase in monokine mRNA levels. Stimulation of a monocytic cell line, THP-1, with staphylococcal exotoxin B and toxic shock syndrome toxin-1 induced a rapid rise in IL-1 beta and TNF-alpha mRNA levels. This response peaked at 1 to 3 h poststimulation and remained detectable at 12 h. Nuclear run-on transcription assays demonstrated that SE cause transcriptional activation of the IL-1 beta and TNF-alpha genes. This transcriptional activation did not require de novo protein synthesis as it was not inhibited by the protein synthesis inhibitor cycloheximide. These results define an important function for Ia molecules as regulators of cytokine gene expression and add to the understanding of the changes in cellular function induced by SE.