Activation of gene expression in human neutrophils by high mobility group box 1 protein

Abstract

High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes nucleosomes and facilitates transcription, was recently identified as a late mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis are associated with increased mortality, and administration of HMGB1 produces acute inflammation in animal models of lung injury and endotoxemia. Neutrophils occupy a critical role in mediating the development of endotoxemia-associated acute lung injury, but previously it was not known whether HMGB1 could influence neutrophil activation. In the present experiments, we demonstrate that HMGB1 increases the nuclear translocation of NF-kappaB and enhances the expression of proinflammatory cytokines in human neutrophils. These proinflammatory effects of HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3-kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil activation are distinct from endotoxin-induced signals, because HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. These findings indicate that HMGB1 is an effective stimulus of neutrophil activation that can contribute to development of a proinflammatory phenotype in diseases characterized by excessively high levels of HMGB1.

HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

“…HMGB1 can induce the secretion of TNF-a and IL-1b from human monocytes and neutrophils. 31,32 However, we did not detect a any direct effect of HMGB1 on the secretion of TGF-b1 from a variety of related cell lines. Other cells that are potential sources of TGF-b1, such as vascular smooth muscle cells, were not assessed.…”

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

“…We and others have shown that ERK activity increases as early as 0.5 to 1 h after ischemia in the middle cerebral artery territory (Alessandrini et al, 1999;Wu et al, 2000). This signaling is potentially linked to TLR2, TLR4, and/or RAGE activation (Ishihara et al, 2003;Park et al, 2003;Taguchi et al, 2000) and is known to promote transcription of cytokines such as TNFa (Fiuza et al, 2003). Tumor necrosis factor a mRNA reportedly increases within 1 h after induction of ischemia in the periinfarct and infarct area, peaks at 12 h, and remains elevated for up to 24 h (Gregersen et al, 2000;Lambertsen et al, 2002Lambertsen et al, , 2005Schroeter et al, 2003;Yang et al, 1999).…”

“…Highmobility group box 1 participates in nucleosome formation and regulation of gene transcription (Park et al, 2003;Stros et al, 2002). High-mobility group box 1 has recently been characterized as a key cytokine Yang et al, 2005).…”

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

“…Extracellular HMGB1 has been shown to cause multiple organ failure and contribute to the pathogenesis of divers disorders including sepsis and acute lung injury [125]. HMGB1 amplifies and extends the inflammatory response by inducing the release of other proinflammatory cytokines from many cell types, including activated macrophages and neutrophil [126]. Elevated levels of HMGB1 are present in the plasma and lung epithelial lining fluids of patients with acute lung injury and in mice exhibiting lung injury-induced by LPS instillation [127].…”

“…In addition, exposure of respiratory epithelial cells to 95% O 2 synergistically increased TNF-α-mediated activation of NF-κB and NF-κB dependent gene expression by a mechanism involving increased activation of IKK [81]. Furthermore, NF-κB plays a critical role in the release of HMGB1 into the extracellular matrix, thereby increasing the proinflammatory activity directly and evoking the production of other proinflammatory cytokines [126]. The precise mechanisms that modulate NF-κB-mediated release of HMGB1 remain unclear because neither the production nor the secretion of HMGB1 is regulated at the transcriptional level [133].…”