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Rigosertib inhibits MEK1-ERK pathway and alleviates lipopolysaccharide-induced sepsis
Yin Wang1, Pengfei Du1, Donghui Jiang1
1Department of Intensive Medicine, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.
Background:
Here, by using the lipopolysaccharide (LPS)-induced mice sepsis model, we treated septic wild-type (WT) mice or MEK1DD mice with rigosertib to evaluate its prospective effects on sepsis.
Methods:
We also generated macrophages derived from bone marrow from WT or MEK1DD mice. These macrophages were pretreated with rigosertib and then induced with LPS or poly I:C.
Results:
Rigosertib suppressed LPS or poly I:C-induced expression of inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6], and IL-23) in WT bone marrow-derived macrophages while failed to affect the upregulation of TNF-α and IL-6 in LPS-treated bone marrow-derived macrophages from MEK1DD mice. Rigosertib promoted survival rate, ameliorated lung injury, and reduced inflammatory cytokine levels in serum of WT septic mice.
Conclusion:
In contrast, the effects of rigosertib on sepsis were abrogated in septic MEK1DD mice, which had inducible constitutive activation of MEK1 signaling. Rigosertib alleviated LPS-induced sepsis inhibits MEK1/ERK signaling pathway.
Insights
Rigosertib effectively treats sepsis in wild-type mice by reducing inflammation and improving survival. Its therapeutic effects are diminished in MEK1DD mice, indicating the MEK1/ERK pathway is crucial for rigosertib
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Sepsis is a life-threatening condition characterized by dysregulated host response to infection.
- Lipopolysaccharide (LPS)-induced mouse sepsis models are widely used to study sepsis pathophysiology.
- MEK1 signaling plays a role in inflammatory responses.
Purpose of the Study:
- To investigate the therapeutic potential of rigosertib in a mouse model of sepsis.
- To elucidate the role of the MEK1/ERK signaling pathway in rigosertib's anti-septic effects.
Main Methods:
- Utilized lipopolysaccharide (LPS)-induced sepsis model in wild-type (WT) and MEK1DD mice.
- Treated septic mice and bone marrow-derived macrophages with rigosertib.
- Assessed inflammatory cytokine levels (TNF-α, IL-6, IL-23) and survival rates.
Main Results:
- Rigosertib suppressed LPS/poly I:C-induced inflammatory cytokines in WT macrophages.
- Rigosertib treatment improved survival, reduced lung injury, and lowered serum cytokine levels in WT septic mice.
- The anti-septic effects of rigosertib were abrogated in MEK1DD mice.
Conclusions:
- Rigosertib demonstrates therapeutic efficacy in sepsis by inhibiting the MEK1/ERK signaling pathway.
- MEK1/ERK pathway activation is critical for rigosertib's beneficial effects in sepsis.
- Rigosertib represents a potential therapeutic agent for sepsis, particularly in cases involving MEK1/ERK pathway modulation.
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