title: Staphylococcal enterotoxin A induction of pro-inflammatory cytokines and lethality in mice is primarily dependent on MyD88.
abstract: Staphylococcal enterotoxin (SE) -induced toxic shock is triggered by inflammatory cytokine signal amplification after SE binding to major histocompatibility complex class II molecules on antigen-presenting cells and T-cell receptors. Identifying host cellular elements contributing to this pro-inflammatory signal amplification is critical for developing a strategy for therapeutic intervention. Myeloid differentiation primary-response protein 88 (MyD88) is an intracellular signalling adaptor protein primarily known for mediating pro-inflammatory cytokine responses. We investigated the role of MyD88 in staphylococcal enterotoxin A (SEA) -treated cell cultures and mouse models of toxic shock. Our results demonstrated that elevated levels of tumour necrosis factor-alpha, interferon-gamma, interleukin-1alpha/beta (IL-1alpha/beta), IL-2 and IL-6 production correlated with up-regulation of MyD88 after treatment of spleen cells and mice with SEA alone or in combination with lipopolysaccharide (LPS). The SEA-induced lethality was also observed in (LPS-independent) D-galactosamine-sensitized mice. While LPS potentiated SEA-induced cytokine responses, D-galactosamine treatment had no additive effect. Most importantly, our results demonstrated that MyD88(-/-) mice were resistant to SEA-induced toxic shock and had reduced pro-inflammatory cytokine responses. These results suggest that SEA-induced lethality is primarily dependent on MyD88. Our findings offer an important insight on potential therapeutic treatment of SEA-induced toxic shock targeting MyD88.
authors.affiliation: Department of Immunology, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA.
authors.forename: Teri L
authors.initials: TL
authors.lastname: Kissner
authors.forename: Emily D
authors.initials: ED
authors.lastname: Cisney
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; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D004768:Enterotoxins / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013210:Staphylococcus / Q000187:drug effects / Q000276:immunology*
chemical_list: D016207:Cytokines; D004768:Enterotoxins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C026066:enterotoxin A, Staphylococcal
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