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

作者：Kissner Teri L; Moisan Lionel; Mann Enrique; Alam Shahabuddin; Ruthel Gordon; Ulrich Robert G; Rebek Mitra; Rebek Julius Jr; Saikh Kamal U^*

来源：Journal of Biological Chemistry, 2011, 286(36): 31385-31396.

DOI：10.1074/jbc.M110.204982

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-1 beta (IL-1 beta) 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.

• 出版日期2011-9-9