Glutathione, polyamine, and lysophosphatidylcholine synthesis pathways are associated with circulating pro-inflammatory cytokines.

Introduction: Pro-inflammatory cytokines are responsible for initiating an effective defense against exogenous pathogens, and their regulation has a vital role in maintaining physiological homeostasis. The involvement of pro-inflammatory cytokines in pathological conditions have been explored in great detail, however, studies investigating metabolic pathways associated with these cytokines under normal homeostatic conditions are scarce.

Objectives: The aim of the current study was to identify metabolites and metabolic pathways associated with circulating pro-inflammatory cytokines under homeostatic conditions using a metabolomics approach.

Methods: The study participants (n = 133) were derived from the Newfoundland Osteoarthritis Study (NFOAS) and the Complex Diseases in the Newfoundland population: Environment and Genetics (CODING) study. Plasma concentrations of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and macrophage migration inhibitory factor (MIF) were assessed by enzyme-linked immunosorbent assay. Targeted metabolomic profiling on fasting plasma samples was performed using Biocrates MxP® Quant 500 kit which measures a total of 630 metabolites. Associations between natural log-transformed metabolite concentrations and metabolite sums/ratios and cytokine levels were assessed using linear regression with adjustment for age, sex, body mass index (BMI), and osteoarthritis status.

Results: Seven metabolites and 11 metabolite sums/ratios were found to be significantly associated with TNF-α, IL-1β, and MIF (all p ≤ 5.13 × 10^- 5) after controlling multiple testing with Bonferroni method, indicating the association between glutathione (GSH), polyamine, and lysophosphatidylcholine (lysoPC) synthesis pathways and these pro-inflammatory cytokines.

Conclusion: GSH, polyamine, and lysoPC synthesis pathways were positively associated with circulating TNF-α, IL-1β, and MIF levels under homeostatic conditions.