title: 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-γR1 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 pro-inflammatory cytokine responses. We also reported that MyD88(-/-) 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-α and IL-1β. 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-α and IL-1β. 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.
authors.affiliation: Department of Immunology, Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, United States of America.
authors.forename: Teri L
authors.initials: TL
authors.lastname: Kissner
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.forename: Shahabuddin
authors.initials: S
authors.lastname: Alam
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: Stefan
authors.initials: S
authors.lastname: Fernandez
authors.forename: Kamal U
authors.initials: KU
authors.lastname: Saikh
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D016207:Cytokines / Q000096:biosynthesis; D004768:Enterotoxins / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016207:Cytokines; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C031818:enterotoxin B, staphylococcal