SEB-induced signaling in macrophages leads to biphasic TNF-alpha.

APCs express MHC-II molecules. Binding of enterotoxins to MHC-II generates a signal resulting in the production of TNF-alpha that mediates toxic shock syndrome. However, the signaling events that lead to TNF-alpha production in macrophages are not well understood. We, for the first time, demonstrate that binding of staphylococcal enterotoxin B to MHC-II results in activation of TNF-alpha-converting enzyme, epidermal growth factor receptor, p38MAPK, and NF-kappaB inducing biphasic TNF-alpha production. Paraformaldehyde-fixed, peptide-specific T cells also activate MHC-II signaling and TNF-alpha induction in peptide-pulsed macrophages. Our results reveal a novel MHC-II signaling and bidirectional macrophage-T cell interaction regulating macrophage functions. This knowledge may help to develop novel, macrophage-directed, therapeutic strategies.