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Published on: December 18, 2010
Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect
Piao Luo1,2, Qian Zhang1,2, Tian-Yu Zhong3
1Artemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, 100700, China.
Background:
Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis.
Methods:
We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide (LPS). We screened for potential protein targets of Cel using activity-based protein profiling (ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown.
Results:
Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS (P < 0.05). Cel bound to Cys424 of pyruvate kinase M2 (PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis (Warburg effect). Cel also bound to Cys106 in high mobility group box 1 (HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin (IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A (LDHA).
Conclusion:
Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.
Insights
Celastrol (Cel) effectively treats sepsis by reducing inflammation and inhibiting the Warburg effect. This natural compound targets key proteins like pyruvate kinase M2 (PKM2) and high mobility group box 1 (HMGB1) to combat life-threatening organ dysfunction.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection.
- Currently, no specific therapies exist for sepsis, highlighting the need for novel treatment strategies.
- Celastrol (Cel), a natural anti-inflammatory compound, shows promise for treating systemic inflammatory diseases.
Purpose of the Study:
- To investigate the pharmacological activity of Celastrol (Cel) in preclinical models of endotoxemia and sepsis.
- To elucidate the molecular mechanisms underlying Cel's therapeutic effects in sepsis.
- To identify specific protein targets of Cel using advanced biochemical screening methods.
Main Methods:
- Evaluated Cel's anti-inflammatory effects in mouse models of endotoxemia and sepsis, as well as in lipopolysaccharide (LPS)-stimulated macrophage cultures.
- Employed activity-based protein profiling (ABPP) to identify potential protein targets of Cel.
- Validated Cel-protein interactions using biophysical techniques, including cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR).
- Determined Cel binding sites through point mutagenesis and assessed functional consequences via gene knockdown.
Main Results:
- Celastrol demonstrated protective effects against lethal endotoxemia and improved survival in sepsis models.
- Cel significantly reduced pro-inflammatory cytokine levels in LPS-treated mice and macrophages (P < 0.05).
- Cel binds to Cys424 of pyruvate kinase M2 (PKM2), inhibiting its activity and suppressing the Warburg effect (aerobic glycolysis).
- Cel also binds to Cys106 of high mobility group box 1 (HMGB1), reducing interleukin-1β (IL-1β) secretion.
- Cel was found to bind to cysteine residues in lactate dehydrogenase A (LDHA).
Conclusions:
- Celastrol exhibits significant anti-inflammatory properties and therapeutic potential in sepsis models.
- Cel's mechanism involves targeting pyruvate kinase M2 (PKM2) and high mobility group box 1 (HMGB1) proteins.
- Inhibition of PKM2 by Cel suppresses the Warburg effect, a metabolic hallmark observed in sepsis.
- Cel's action on HMGB1 reduces the secretion of pro-inflammatory cytokine IL-1β, contributing to its anti-septic effects.
