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Activation of peroxisome proliferator-activated receptor ? by rosiglitazone inhibits lipopolysaccharide-induced release of high mobility group box 1.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are shown to modulate the pathological status of sepsis by regulating the release of high mobility group box 1 (HMGB1), a well-known late proinflammatory mediator of sepsis. Ligand-activated PPARs markedly inhibited lipopolysaccharide- (LPS) induced release of HMGB1 in RAW 264.7 cells. Among the ligands of PPAR, the effect of rosiglitazone, a specific ligand for PPAR?, was superior in the inhibition of HMGB1 release induced by LPS. This effect was observed in cells that received rosiglitazone before LPS or after LPS treatment, indicating that rosiglitazone is effective in both treatment and prevention. Ablation of PPAR? with small interfering RNA or GW9662-mediated inhibition of PPAR? abolished the effect of rosiglitazone on HMGB1 release. Furthermore, the overexpression of PPAR? markedly potentiated the inhibitory effect of rosiglitazone on HMGB1 release. In addition, rosiglitazone inhibited LPS-induced expression of Toll-like receptor 4 signal molecules, suggesting a possible mechanism by which rosiglitazone modulates HMGB1 release. Notably, the administration of rosiglitazone to mice improved survival rates in an LPS-induced animal model of endotoxemia, where reduced levels of circulating HMGB1 were demonstrated. Taken together, these results suggest that PPARs play an important role in the cellular response to inflammation by inhibiting HMGB1 release.

SUBMITTER: Hwang JS

PROVIDER: S-EPMC3539392 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Activation of peroxisome proliferator-activated receptor γ by rosiglitazone inhibits lipopolysaccharide-induced release of high mobility group box 1.

Hwang Jung Seok JS Kang Eun Sil ES Ham Sun Ah SA Yoo Taesik T Lee Hanna H Paek Kyung Shin KS Park Chankyu C Kim Jin-Hoi JH Lim Dae-Seog DS Seo Han Geuk HG

Mediators of inflammation 20121220

Peroxisome proliferator-activated receptors (PPARs) are shown to modulate the pathological status of sepsis by regulating the release of high mobility group box 1 (HMGB1), a well-known late proinflammatory mediator of sepsis. Ligand-activated PPARs markedly inhibited lipopolysaccharide- (LPS) induced release of HMGB1 in RAW 264.7 cells. Among the ligands of PPAR, the effect of rosiglitazone, a specific ligand for PPARγ, was superior in the inhibition of HMGB1 release induced by LPS. This effect ...[more]

PMID: 23316104

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Project description:Essentials APC elicits cytoprotective responses in endothelial cells via EPCR-dependent cleavage of PAR1. APC inhibits LPS-mediated translocation and extracellular secretion of HMGB1 in endothelial cells. Signaling activity of APC inhibits LPS-mediated acetylation of HMGB1 by epigenetic mechanisms. APC inhibits LPS-mediated HMGB1 expression in CD31-positive endothelial cells in cremaster muscle. SUMMARY: Background Activated protein C (APC) inhibits high-mobility group box 1 (HMGB1) signaling and its lipopolysaccharide (LPS)-mediated release by endothelial protein C receptor (EPCR)-dependent activation of protease-activated receptor 1 (PAR1) in endothelial cells. Post-translational acetylation is known to modulate the subcellular localization of HMGB1, and its hyperacetylated form is translocated to the cytoplasm of innate immune cells before being secreted into the extracellular space. Objective To determine whether APC inhibits LPS-mediated HMGB1 secretion from endothelial cells by modulating its acetylation status. Methods The subcellular localization of HMGB1 in LPS-treated endothelial cells was monitored in the absence and presence of APC by western blot analysis of fractionated cell lysates and confocal immunofluorescence microscopy. Results Both western blot and immunofluorescence data indicated that APC effectively inhibits LPS-mediated translocation of HMGB1 from the nucleus to the cytoplasm by EPCR-dependent and PAR1-dependent mechanisms. When EPCR was ligated by the Gla-domain of protein C/APC, thrombin also inhibited LPS-mediated HMGB1 translocation. Further studies revealed that APC inhibits the translocation of HMGB1 from the nucleus to the cytoplasm by inhibiting LPS-mediated hyperacetylation of HMGB1 by (de)acetylating enzymes. Furthermore, the translocated HMGB1 was found to be associated with lysosome-associated membrane protein 1 in LPS-treated endothelial cells. The in vivo relevance of these findings was investigated in the mouse cremaster muscle, and this demonstrated that both wild-type APC and a signaling-selective mutant of APC inhibit LPS-mediated HMGB1 expression and translocation in CD31-positive endothelial cells. Conclusion These results suggest that APC inhibits LPS-mediated cytoplasmic translocation and secretion of HMGB1 in endothelial cells by epigenetic mechanisms.

Project description:The release of high mobility group box 1 (HMGB1) induced by inflammatory signals acts as a cellular alarmin to trigger a chain of inflammatory responses. Although the inflammatory actions of HMGB1 are well studied, less is known about the therapeutic agents that can impede its release. This study investigated whether the isoflavonoid formononetin can modulate HMGB1 release in cellular inflammatory responses.RAW264.7 murine macrophages were exposed to lipopolysaccharide (LPS) in the presence or absence of formononetin. The levels of HMGB1 release, sirtuin 1 (SIRT1) expression, and HMGB1 acetylation were analyzed by immunoblotting and real-time polymerase chain reaction. The effects of resveratrol and sirtinol, an activator and inhibitor of SIRT1, respectively, on LPS-induced HMGB1 release were also evaluated.Formononetin modulated cellular inflammatory responses by suppressing the release of HMGB1 by macrophages exposed to LPS. In RAW264.7 cells, formononetin significantly attenuated LPS-induced release of HMGB1 into the extracellular environment, which was accompanied by a reduction in its translocation from the nucleus to the cytoplasm. In addition, formononetin significantly induced mRNA and protein expression of SIRT1 in a peroxisome proliferator-activated receptor ? (PPAR?)-dependent manner. These effects of formononetin were dramatically attenuated in cells treated with small interfering RNA (siRNA) against PPAR? or with GSK0660, a specific inhibitor of PPAR?, indicating that PPAR? is involved in formononetin-mediated SIRT1 expression. In line with these effects, formononetin-mediated inhibition of HMGB1 release in LPS-treated cells was reversed by treatment with SIRT1-targeting siRNA or sirtinol, a SIRT1 inhibitor. By contrast, resveratrol, a SIRT1 activator, further potentiated the inhibitory effect of formononetin on LPS-induced HMGB1 release, revealing a possible mechanism by which formononetin regulates HMGB1 release through SIRT1. Furthermore, modulation of SIRT1 expression by transfection of SIRT1- or PPAR?-targeting siRNA significantly counteracted the inhibitory effects of formononetin on LPS-induced HMGB1 acetylation, which was responsible for HMGB1 release.This study shows for the first time that formononetin inhibits HMGB1 release by decreasing HMGB1 acetylation via upregulating SIRT1 in a PPAR?-dependent manner. Formononetin consequently exhibits anti-inflammatory activity. Identification of agents, such as formononetin, which can block HMGB1 release, may help to treat inflammation-related disorders.

Project description:Although glucocorticoids (GC) represent the most frequently used immunosuppressive drugs, their effects are still not well understood. In our previous studies, we have shown that treatment of monocytes with GC does not cause a global suppression of monocytic effector functions, but rather induces differentiation of a specific anti-inflammatory phenotype. The anti-inflammatory role of peroxisome proliferator-activated receptor (PPAR)-? has been extensively studied during recent years. However, a relationship between GC treatment and PPAR-? expression in macrophages has not been investigated so far. Studies using PPAR-?-deficient mice have frequently provided controversial results. A potential reason is the use of primary cells, which commonly represent inhomogeneous populations burdened with side effects and influenced by bystander cells. To overcome this constraint, we established ER-Hoxb8-immortalized bone marrow-derived macrophages from Ppargfl/fl and LysM-Cre Ppargfl/fl mice in this study. In contrast to primary macrophages, the ER-Hoxb8 system allows the generation of a homogeneous and well-defined population of resting macrophages. We could show that the loss of PPAR-? resulted in delayed kinetic of differentiation of monocytes into macrophages as assessed by reduced F4/80, but increased Ly6C expression in early phases of differentiation. As expected, PPAR-?-deficient macrophages displayed an increased pro-inflammatory phenotype upon long-term LPS stimulation characterized by an elevated production of pro-inflammatory cytokines TNF-?, IL1-?, IL-6, IL-12 and a reduced production of anti-inflammatory cytokine IL-10 compared to PPAR-? WT cells. Moreover, PPAR-?-deficient macrophages showed impaired phagocytosis. GC treatment of macrophages led to the upregulation of PPAR-? expression. However, there were no differences in GC-induced suppression of cytokines between both cell types, implicating a PPAR-?-independent mechanism. Intriguingly, GC treatment resulted in an increased in vitro migration only in PPAR-?-deficient macrophages. Performing a newly developed in vivo cell-tracking experiment, we could confirm that GC induces an increased recruitment of PPAR-? KO, but not PPAR-? WT macrophages to the site of inflammation. Our findings suggest a specific effect of PPAR-? on GC-induced migration in macrophages. In conclusion, we could demonstrate that PPAR-? exerts anti-inflammatory activities and shapes macrophage functions. Moreover, we identified a molecular link between GC and PPAR-? and could show for the first time that PPAR-? modulates GC-induced migration in macrophages.

Dataset Information

Activation of peroxisome proliferator-activated receptor ? by rosiglitazone inhibits lipopolysaccharide-induced release of high mobility group box 1.

Publications

Activation of peroxisome proliferator-activated receptor γ by rosiglitazone inhibits lipopolysaccharide-induced release of high mobility group box 1.

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