Ketamine promotes inflammation through increasing TLR4 expression in RAW264.7 cells

Area of Science:

• Immunology
• Pharmacology

Background:

• Ketamine (KTM), an N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits anti-inflammatory properties.
• However, some patients experience exacerbated pro-inflammatory reactions following KTM anesthesia.
• The precise mechanism behind KTM's pro-inflammatory effects requires elucidation.

Purpose of the Study:

• To investigate the underlying mechanism of ketamine's pro-inflammatory effects.
• To determine the role of NMDA receptors and Toll-like receptor 4 (TLR4) in KTM-induced inflammation.

Main Methods:

• RAW264.7 macrophage cells were treated with KTM and NMDA, followed by lipopolysaccharide (LPS) stimulation.
• Expression levels of IL-6, TNF-α, NMDA receptors, and TLR4 were quantified using RT-PCR, ELISA, and flow cytometry.
• TLR4 function was assessed using siRNA-mediated gene silencing.

Main Results:

• KTM alone increased TLR4 expression in RAW264.7 cells but did not elevate IL-6 or TNF-α levels.
• In the presence of LPS, KTM significantly enhanced IL-6 and TNF-α expression compared to LPS alone.
• NMDA did not affect IL-6/TNF-α expression or alter KTM's effect in LPS-challenged cells.
• Silencing TLR4 abolished the enhanced IL-6 and TNF-α expression induced by KTM in LPS-stimulated cells.

Conclusions:

• Ketamine accelerates LPS-induced inflammation by upregulating TLR4 expression.
• This pro-inflammatory effect of KTM is independent of NMDA receptor activity.
• Targeting TLR4 may mitigate ketamine-induced inflammatory side effects.