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

Hwang JS, Kang ES, Ham SA, Yoo T, Lee H, Paek KS, Park C, Kim JH, Lim DS, Seo HG - Mediators Inflamm. (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.

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 PPARγ, 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 PPARγ with small interfering RNA or GW9662-mediated inhibition of PPARγ abolished the effect of rosiglitazone on HMGB1 release. Furthermore, the overexpression of PPARγ 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.

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Rosiglitazone prevents endotoxin lethality by attenuating HMGB1 release in vivo. (a) BALB/c mice (n = 10-11 per group) were injected with a single dose of rosiglitazone (10 mg/kg, i.p.) with or without GW9662 (1 mg/kg, i.p.), followed 30 min later by a lethal infusion of endotoxin (LPS, 10 mg/kg, i.p.). (b) BALB/c mice (n = 4 per group) infused with endotoxin (LPS, 10 mg/kg, i.p.) were treated with rosiglitazone (10 mg/kg, i.p.) 0, 1, 3, 6, and 12 h later. Survival was monitored daily for up to 2 weeks. (c) In a parallel group of rosiglitazone-administered mice, circulating levels of HMGB1 were detected by Western blot analysis using sera prepared from samples collected at 20 h post-LPS injection. Representative blots from four independent experiments and densitometric measurements are shown. Ponceau S staining was used as a loading control. The results are expressed as the means ± S.E. (n = 3). *P < 0.01 compared to the untreated group; #P < 0.01 compared to the LPS-treated group; ‡P < 0.05 compared to the LPS plus rosiglitazone-treated group.
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fig6: Rosiglitazone prevents endotoxin lethality by attenuating HMGB1 release in vivo. (a) BALB/c mice (n = 10-11 per group) were injected with a single dose of rosiglitazone (10 mg/kg, i.p.) with or without GW9662 (1 mg/kg, i.p.), followed 30 min later by a lethal infusion of endotoxin (LPS, 10 mg/kg, i.p.). (b) BALB/c mice (n = 4 per group) infused with endotoxin (LPS, 10 mg/kg, i.p.) were treated with rosiglitazone (10 mg/kg, i.p.) 0, 1, 3, 6, and 12 h later. Survival was monitored daily for up to 2 weeks. (c) In a parallel group of rosiglitazone-administered mice, circulating levels of HMGB1 were detected by Western blot analysis using sera prepared from samples collected at 20 h post-LPS injection. Representative blots from four independent experiments and densitometric measurements are shown. Ponceau S staining was used as a loading control. The results are expressed as the means ± S.E. (n = 3). *P < 0.01 compared to the untreated group; #P < 0.01 compared to the LPS-treated group; ‡P < 0.05 compared to the LPS plus rosiglitazone-treated group.

Mentions: To further investigate the in vivo relevance of these in vitro results, an initial evaluation of rosiglitazone as a therapeutic agent was performed using a standard model of murine endotoxemia. Injection of LPS dramatically increased the mortality of mice, whereas the administration of rosiglitazone prior to LPS treatment significantly improved the survival rates (Figure 6(a)). This effect of rosiglitazone was significantly reduced in the presence of GW9662, indicating the involvement of PPARγ in the rosiglitazone-mediated improvement of survival rates. Late deaths in rosiglitazone and/or GW9662-administered animals were not observed during the 2 weeks following endotoxin injection (data not shown), indicating that administration of rosiglitazone conferred protection to mice against lethal endotoxemia. Furthermore, the posttreatment of rosiglitazone after LPS also improved the survival rates until after 3 h (Figure 6(b)), demonstrating that rosiglitazone has an extended therapeutic window. Because endotoxin lethality is corelated to HMGB1 release [3, 4, 6–8], the effects of rosiglitazone on the level of circulating HMGB1 in blood were determined. HMGB1 blood levels significantly increased by LPS injection, whereas the administration of rosiglitazone almost completely abolished the release of HMGB1 into the blood, which was reversed by the presence of GW9662 (Figure 6(c)). These results indicated that rosiglitazone prevents endotoxin lethality in vivo by blocking HMGB1 release.


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

Hwang JS, Kang ES, Ham SA, Yoo T, Lee H, Paek KS, Park C, Kim JH, Lim DS, Seo HG - Mediators Inflamm. (2012)

Rosiglitazone prevents endotoxin lethality by attenuating HMGB1 release in vivo. (a) BALB/c mice (n = 10-11 per group) were injected with a single dose of rosiglitazone (10 mg/kg, i.p.) with or without GW9662 (1 mg/kg, i.p.), followed 30 min later by a lethal infusion of endotoxin (LPS, 10 mg/kg, i.p.). (b) BALB/c mice (n = 4 per group) infused with endotoxin (LPS, 10 mg/kg, i.p.) were treated with rosiglitazone (10 mg/kg, i.p.) 0, 1, 3, 6, and 12 h later. Survival was monitored daily for up to 2 weeks. (c) In a parallel group of rosiglitazone-administered mice, circulating levels of HMGB1 were detected by Western blot analysis using sera prepared from samples collected at 20 h post-LPS injection. Representative blots from four independent experiments and densitometric measurements are shown. Ponceau S staining was used as a loading control. The results are expressed as the means ± S.E. (n = 3). *P < 0.01 compared to the untreated group; #P < 0.01 compared to the LPS-treated group; ‡P < 0.05 compared to the LPS plus rosiglitazone-treated group.
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Related In: Results  -  Collection

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fig6: Rosiglitazone prevents endotoxin lethality by attenuating HMGB1 release in vivo. (a) BALB/c mice (n = 10-11 per group) were injected with a single dose of rosiglitazone (10 mg/kg, i.p.) with or without GW9662 (1 mg/kg, i.p.), followed 30 min later by a lethal infusion of endotoxin (LPS, 10 mg/kg, i.p.). (b) BALB/c mice (n = 4 per group) infused with endotoxin (LPS, 10 mg/kg, i.p.) were treated with rosiglitazone (10 mg/kg, i.p.) 0, 1, 3, 6, and 12 h later. Survival was monitored daily for up to 2 weeks. (c) In a parallel group of rosiglitazone-administered mice, circulating levels of HMGB1 were detected by Western blot analysis using sera prepared from samples collected at 20 h post-LPS injection. Representative blots from four independent experiments and densitometric measurements are shown. Ponceau S staining was used as a loading control. The results are expressed as the means ± S.E. (n = 3). *P < 0.01 compared to the untreated group; #P < 0.01 compared to the LPS-treated group; ‡P < 0.05 compared to the LPS plus rosiglitazone-treated group.
Mentions: To further investigate the in vivo relevance of these in vitro results, an initial evaluation of rosiglitazone as a therapeutic agent was performed using a standard model of murine endotoxemia. Injection of LPS dramatically increased the mortality of mice, whereas the administration of rosiglitazone prior to LPS treatment significantly improved the survival rates (Figure 6(a)). This effect of rosiglitazone was significantly reduced in the presence of GW9662, indicating the involvement of PPARγ in the rosiglitazone-mediated improvement of survival rates. Late deaths in rosiglitazone and/or GW9662-administered animals were not observed during the 2 weeks following endotoxin injection (data not shown), indicating that administration of rosiglitazone conferred protection to mice against lethal endotoxemia. Furthermore, the posttreatment of rosiglitazone after LPS also improved the survival rates until after 3 h (Figure 6(b)), demonstrating that rosiglitazone has an extended therapeutic window. Because endotoxin lethality is corelated to HMGB1 release [3, 4, 6–8], the effects of rosiglitazone on the level of circulating HMGB1 in blood were determined. HMGB1 blood levels significantly increased by LPS injection, whereas the administration of rosiglitazone almost completely abolished the release of HMGB1 into the blood, which was reversed by the presence of GW9662 (Figure 6(c)). These results indicated that rosiglitazone prevents endotoxin lethality in vivo by blocking HMGB1 release.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.

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 PPARγ, 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 PPARγ with small interfering RNA or GW9662-mediated inhibition of PPARγ abolished the effect of rosiglitazone on HMGB1 release. Furthermore, the overexpression of PPARγ 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.

Show MeSH
Related in: MedlinePlus