Suberoylanilide hydroxamic acid (SAHA) as an agent to attenuate Toll-like receptor 4–induced septic shock

Abstract

Severe sepsis and septic shock are still associated with high mortality despite the advancement of antibiotics and critical care. Macrophages detect bacterial lipopolysaccharide (LPS) by a mechanism mediated by Toll-like receptor 4 (TLR4). This receptor causes activation of proinflammatory cascade and production of proteins and cytokines, such as myeloid differentiation primary response gene 88 (MyD88), interleukin (IL)-1 (including IL-1 receptor-associated kinase [IRAK]-1), tumor necrosis factor receptor-associated factor 6, and nuclear factor-κB (NF-κB), which can lead to robust and potentially exaggerated immune response of the body. In a paper recently published in the Journal of Surgical Research, Chong et al. show that suberoylanilide hydroxamic acid (SAHA) can improve survival of LPS-induced septic shock in mice, but the mechanism of this has largely been unknown [ [1] Chong W. Li Y. Liu B. et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates Toll-like receptor 4 signaling in lipopolysaccharide-stimulated mouse macrophages.. J Surg Res. 2012; 178: 851 Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar ]. In this in vitro study, they demonstrated that treatment of SAHA significantly reduced the MyD88 and IRAK-1 production as well as the nuclear translocation of NF-κB and, eventually, production of tumor necrosis factor (TNF)-α and IL-6, thus attenuating the LPS/TLR4 signaling cascade by inhibiting the upstream proteins. It was also demonstrated that SAHA acetylated heat shock protein (HSP) 90, which is another component of the proinflammatory pathway. Acetylation of HSP90 inhibits its interaction with IRAK1, which in turn leads to degradation of IRAK-1, thus potentially causing impairment of TLR4-activated inflammatory pathway [ [1] Chong W. Li Y. Liu B. et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates Toll-like receptor 4 signaling in lipopolysaccharide-stimulated mouse macrophages.. J Surg Res. 2012; 178: 851 Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar ]. Histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates Toll-like receptor 4 signaling in lipopolysaccharide-stimulated mouse macrophagesJournal of Surgical ResearchVol. 178Issue 2PreviewWe have previously demonstrated that pretreatment and posttreatment of animals with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can improve survival in a mouse model of lipopolysaccharide (LPS)-induced severe shock. This study was designed to assess whether SAHA affects LPS/Toll-like receptor 4 signaling through acetylation of heat shock protein 90 (HSP90) and degradation of its client protein interleukin-1 receptor–associated kinase 1 (IRAK1). Full-Text PDF