Activation of MyD88 Signaling upon Staphylococcal Enterotoxin Binding to MHC Class II Molecules
Abstract
Ligands binding to Toll-like receptor (TLR), interleukin 1 receptor (IL-1R), or IFN-cR1 are known to trigger MyD88-mediated signaling, which activates pro-inflammatory cytokine responses. Recently we reported that staphylococcal enterotoxins (SEA or SEB), which bind to MHC class II molecules on APCs and cross link T cell receptors, activate MyD88-mediated proinflammatory cytokine responses. We also reported that MyD882/2 mice were resistant to SE- induced toxic shock and had reduced levels of serum cytokines. In this study, we investigated whether MHC class II- SE interaction by itself is sufficient to activate MyD88 in MHC class II+ cells and induce downstream pro-inflammatory signaling and production of cytokines such as TNF-a and IL-1b. Here we report that human monocytes treated with SEA, SEB, or anti-MHC class II monoclonal antibodies up regulated MyD88 expression, induced activation of NF-kB, and increased expression of IL-1R1 accessory protein, TNF-a and IL-1b. MyD88 immunoprecipitated from cell extracts after SEB stimulation showed a greater proportion of MyD88 phosphorylation compared to unstimulated cells indicating that MyD88 was a component of intracellular signaling. MyD88 downstream proteins such as IRAK4 and TRAF6 were also up regulated in monocytes after SEB stimulation. In addition to monocytes, primary B cells up regulated MyD88 in response to SEA or SEB stimulation. Importantly, in contrast to primary B cells, MHC class II deficient T2 cells had no change of MyD88 after SEA or SEB stimulation, whereas MHC class II-independent activation of MyD88 was elicited by CpG or LPS. Collectively, these results demonstrate that MHC class II utilizes a MyD88-mediated signaling mechanism when in contact with ligands such as SEs to induce pro-inflammatory cytokines.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 20, 2011
- Accession Number
- ADA536161
Entities
People
- Gordon T. Ruthel
- Kamal U. Saikh
- Robert G Ulrich
- Shahabuddin Alam
- Stefan Fernandez
- Teri L. Kissner
Organizations
- United States Army Medical Research Institute of Infectious Diseases