Glucan phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-κB activation

Abstract

phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-B activation. Am J Physiol Heart Circ Physiol 301: H848 -H855, 2011. First published June 3, 2011 doi:10.1152/ajpheart.01007.2010.-Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. High-mobility group box 1 (HMGB1) serves as a late mediator of lethality in sepsis. We have reported that glucan phosphate (GP) attenuates cardiac dysfunction and increases survival in cecal ligation and puncture (CLP)-induced septic mice. In the present study, we examined the effect of GP on HMGB1 translocation from the nucleus to the cytoplasm in the myocardium of septic mice. GP was administered to mice 1 h before induction of CLP. Sham-operated mice served as control. The levels of HMGB1, Toll-like receptor 4 (TLR4), and NF-B binding activity were examined. In an in vitro study, H9C2 cardiomyoblasts were treated with lipopolysaccharide (LPS) in the presence or absence of GP. H9C2 cells were also transfected with Ad5-IB␣ mutant, a super repressor of NF-B activity, before LPS stimulation. CLP significantly increased the levels of HMGB1, TLR4, and NF-B binding activity in the myocardium. In contrast, GP administration attenuated CLP-induced HMGB1 translocation from the nucleus to the cytoplasm and reduced CLP-induced increases in TLR4 and NF-B activity in the myocardium. In vitro studies showed that GP prevented LPS-induced HMGB1 translocation and NF-B binding activity. Blocking NF-B binding activity by Ad5-IB␣ attenuated LPSinduced HMGB1 translocation. GP administration also reduced the LPS-stimulated interaction of HMGB1 with TLR4. These data suggest that attenuation of HMGB1 translocation by GP is mediated through inhibition of NF-B activation in CLP-induced sepsis and that activation of NF-B is required for HMGB1 translocation.high-mobility group box 1; myocardium; nuclear factor-B HIGH-MOBILITY GROUP BOX 1 (HMGB1) is an evolutionarily conserved protein present in the nucleus of almost all eukaryotic cells where it functions to stabilize nucleosomes and acts as a transcription factor (4,14,25,28). Recent evidence suggests that HMGB1 is an important danger-associated molecular pattern (DAMP) (14, 28) and is actively secreted by activated macrophages and released from necrotic (25) and damaged tissues (4). In vivo neutralization of HMGB1 by specific antibodies protects mice against lethal endotoxemia and sepsis (28), as well as endotoxin-induced acute lung injury (29). More significantly, anti-HMGB1 antibodies rescued mice from lethal sepsis even when the first dose of antibodies was given as late as 24 h after cecal ligation and puncture (CLP) surgery (29). These data suggest that HMGB1 serves as a late mediator of lethality in sepsis (6,28). In vitro studies have demonstrated that the HMGB1-stimulated inflammatory response could be mediated through receptors for advanced glycation end products (RAGE) (27), Toll-like receptor 2 (TLR2), TLR4 (23, 24), and TLR9 (26).TLR-mediated sig...

Innate immunity and cardiomyocytes in ischemic heart disease

“…Viable cardiomyocytes may also actively secrete HMGB1 under stresses, such as the stimulation of LPS (Xu et al, 2010), though the secretory mechanism remains unclear. Translocation of HBMG1 from nuclei to cytosol was observed as well in stressed cardiomyocytes (Funayama et al, 2013; Ha et al, 2011). …”

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

“…It has been reported that LPS-induced activation of NF-kB plays a pivotal role in HMGB1 release from cultured macrophages (34). The inhibition of NF-kB activation with an adenovirus-expressing IkBa mutation can attenuate HMGB1 translocation in cultured cells, as well as in a cecal ligation and puncture-induced animal model of sepsis (66). In addition, inhibitors of IKKa and IKKb have been shown to inhibit HMGB1-induced chemotaxis (67).…”

Tannic acid modulates NFκB signaling pathway and skin inflammation in NC/Nga mice through PPARγ expression

“…The high mobility group protein (HMG)B1, a nuclear protein secreted by immune cells, such as macrophages and dendritic cells, is released into extracellular space, triggering inflammatory immune response, tumor metastasis and autoimmune disease. Extracellular HMGB1 interacts with a multi ligand-receptor for advanced glycation end products (RAGE) leading to the activation of nuclear factor (NF)jB proinflammatory signaling, thereby triggering a variety of inflammatory cytokines such as interleukin (IL)-1b, tumor necrosis factor (TNF)a, IL-4, IL-6 and interferon (IFN)c [5]. Moreover, the elevated levels of cytokines can further induce NFjB activation and thereby worsening the disease condition.…”