title: A small molecule that mimics the BB-loop in the Toll interleukin-1 (IL-1) receptor domain of MyD88 attenuates staphylococcal enterotoxin B-induced pro-inflammatory cytokine production and toxicity in mice.
abstract: Toxic shock syndrome (TSS) is a clinical consequence of the profound amplification of host pro-inflammatory cytokine signaling that results from staphylococcal enterotoxin (SE) exposure. We recently reported that MyD88(-/-) mice were resistant to SEA or SEB toxic shock and displayed reduced levels of pro-inflammatory cytokines in their serum. Here we report that SEB stimulation of total mononuclear cells up-regulated MyD88 in monocytes and T cells. Further, MyD88 gene silencing in primary human cells using siRNA prevented SEB or SEB plus lipopolysaccharide (LPS) induction of interleukin-1β (IL-1β) transcriptional activation, suggesting that MyD88-mediated signaling is an essential component of SEB toxicity. We synthesized small molecules that mimic the conserved BB-loop in the Toll/IL-1 receptor (TIR) domain of MyD88. In primary human cells, these mimetics attenuated SEB-induced pro-inflammatory cytokine production. SEB stimulation of primary cells with mimetic affected newly synthesized MyD88 and downstream signaling components. Furthermore, LPS-induced MyD88 signaling was likewise inhibited in a cell-based reporter assay. More importantly, administration of mimetic reduced cytokine responses and increased survivability in a murine SEB challenge model. Collectively, these results suggest that MyD88 BB-loop mimetics interfere with SEB-induced pro-inflammatory signaling and toxicity, thus offering a potential approach in the therapy of toxic shock.
authors.affiliation: Department of Immunology, Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
authors.forename: Teri L
authors.initials: TL
authors.lastname: Kissner
authors.forename: Lionel
authors.initials: L
authors.lastname: Moisan
authors.forename: Enrique
authors.initials: E
authors.lastname: Mann
authors.forename: Shahabuddin
authors.initials: S
authors.lastname: Alam
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: Mitra
authors.initials: M
authors.lastname: Rebek
authors.forename: Julius
authors.initials: J
authors.lastname: Rebek
authors.forename: Kamal U
authors.initials: KU
authors.lastname: Saikh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D018716:Molecular Mimicry; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017472:Receptors, Interleukin-1 / Q000737:chemistry; D012772:Shock, Septic / Q000188:drug therapy*
chemical_list: D016207:Cytokines; D004768:Enterotoxins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010455:Peptides; D017472:Receptors, Interleukin-1; C031818:enterotoxin B, staphylococcal