Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses

Area of Science:

• Biochemistry
• Immunology
• Cell Biology

Background:

• Citrate is a key metabolic intermediate and anticoagulant.
• ATP-citrate lyase is crucial for inflammation, but exogenous citrate's role is unclear.
• Citrate's dual role as metabolite and calcium chelator suggests modulation of inflammatory signaling.

Purpose of the Study:

• To investigate how citrate affects monocyte inflammatory responses to lipopolysaccharide (LPS).
• To determine the impact of clinically relevant citrate levels on pro-inflammatory cytokine production.
• To elucidate the mechanisms underlying citrate's modulation of inflammatory signaling cascades.

Main Methods:

• Utilized THP-1 human acute monocytic leukemia cell line.
• Assessed LPS-induced tumor necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) transcript levels.
• Employed IL-8-luciferase reporter assays and histone acetylation analysis.
• Investigated the role of ATP-citrate lyase using tricarballylic acid.

Main Results:

• Citrate inhibited TNF-α and IL-8 in normal calcium conditions (0.4 mM).
• Citrate augmented TNF-α and IL-8 in high calcium conditions (1.4 mM), independent of chelation.
• Augmentation was linked to ATP-citrate lyase metabolism and involved transcriptional regulation and histone acetylation.
• Citrate demonstrated a dual role, inhibiting or augmenting cytokine production.

Conclusions:

• Citrate modulates inflammatory gene transactivation, leading to both inhibition and augmentation of pro-inflammatory cytokine production.
• The observed effects are dependent on calcium concentration and citrate metabolism via ATP-citrate lyase.
• Citrate's anticoagulant use may influence immune function through complex interactions with inflammatory pathways.