Rigosertib inhibits MEK1-ERK pathway and alleviates lipopolysaccharide-induced sepsis

Abstract

Background: Here, by using the lipopolysaccharide (LPS)-induced mice sepsis model, we treated septic wild-type (WT) mice or MEK1^DD mice with rigosertib to evaluate its prospective effects on sepsis.

Methods: We also generated macrophages derived from bone marrow from WT or MEK1^DD 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 MEK1^DD 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 MEK1^DD mice, which had inducible constitutive activation of MEK1 signaling. Rigosertib alleviated LPS-induced sepsis inhibits MEK1/ERK signaling pathway.

Keywords: LPS; MEK1/ERK; rigosertib; sepsis.