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-alpha), interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta), 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 (R) 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-alpha, IL-1 beta, and MIF (all p <= 5.13 x 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-alpha, IL-1 beta, and MIF levels under homeostatic conditions.