Prior Toll-like receptor 3 stimulation abolishes the ability of a MAPK/ERK kinase inhibitor to increase lipopolysaccharide-induced nitric oxide production concomitant with tumor necrosis factor-α suppression.

Authors

Ryota Hashimoto, Yaojia Wu, Kaily Fujimoto, Haruto Shintani, Hiroshi Koide, Youichi Katoh

Published in

The Journal of pharmacology and experimental therapeutics. Volume 393. Issue 9. Pages 105013. Aug 17, 2026. Epub Aug 17, 2026.

Abstract

Lipopolysaccharide (LPS) is an endotoxin that can trigger multiple types of acute organ failure by increasing the production of nitric oxide (NO), which is synthesized by inducible NO synthase (iNOS) in macrophages through increased production of tumor necrosis factor (TNF)-α, interferon gamma, and interleukin-12. We have reported that an inhibitor of MAPK/ERK kinase (MEK), which is activated by LPS, increased the mortality rate in LPS-treated mice through enhanced NO production. However, a strategy to prevent lethal NO production by MEK inhibitors, which are used as anticancer agents, remains unclear. In the present study, we examined whether prestimulation of Toll-like receptors (TLRs) influences NO production by a MEK inhibitor in the presence of LPS because LPS is a ligand of TLR4 and macrophages acquire tolerance through repeated TLR stimulation. The MEK inhibitor increased iNOS expression and NO production in LPS-stimulated mouse macrophages. While pretreatment with TLR3, TLR7/8, or TLR9 agonists abolished the increase in iNOS expression, the subsequent increase in NO production was confirmed to be suppressed by TLR3 stimulation. The MEK inhibitor also suppressed the serum levels of both NO and TNF-α in mice pretreated with the TLR3 agonist poly I:C followed by LPS administration. Both iNOS expression and NO production depended on the TNF-α concentration in mouse macrophages treated with interferon gamma and interleukin-12. These results suggest that the ability of MEK inhibitors to increase NO production in mice treated with LPS is abolished by prior TLR3 stimulation, which is associated with the suppression of TNF-α production. SIGNIFICANCE STATEMENT: A MAPK/ERK kinase inhibitor increased nitric oxide production in lipopolysaccharide-treated mice; however, prior Toll-like receptor 3 stimulation abolished this effect, accompanied by a reduction in tumor necrosis factor-α production. Prior Toll-like receptor 3 stimulation may contribute to a potential strategy to prevent lethal nitric oxide production by MAPK/ERK kinase inhibitors in mice treated with lipopolysaccharide.

PMID:
42700643
Bibliographic data and abstract were imported from PubMed on 06 Sep 2026.

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