d-Amino acids differentially trigger an inflammatory environment in vitro
Document Type
Article
Publication Date
2-3-2024
Abstract
Studies in vivo have demonstrated that the accumulation of d-amino acids (d-AAs) is associated with age-related diseases and increased immune activation. However, the underlying mechanism(s) of these observations are not well defined. The metabolism of d-AAs by d-amino oxidase (DAO) produces hydrogen peroxide (H2O2), a reactive oxygen species involved in several physiological processes including immune response, cell differentiation, and proliferation. Excessive levels of H2O2 contribute to oxidative stress and eventual cell death, a characteristic of age-related pathology. Here, we explored the molecular mechanisms of d-serine (d-Ser) and d-alanine (d-Ala) in human liver cancer cells, HepG2, with a focus on the production of H2O2 the downstream secretion of pro-inflammatory cytokine and chemokine, and subsequent cell death. In HepG2 cells, we demonstrated that d-Ser decreased H2O2 production and induced concentration-dependent depolarization of mitochondrial membrane potential (MMP). This was associated with the upregulation of activated NF-кB, pro-inflammatory cytokine, TNF-α, and chemokine, IL-8 secretion, and subsequent apoptosis. Conversely, d-Ala-treated cells induced H2O2 production, and were also accompanied by the upregulation of activated NF-кB, TNF-α, and IL-8, but did not cause significant apoptosis. The present study confirms the role of both d-Ser and d-Ala in inducing inflammatory responses, but each via unique activation pathways. This response was associated with apoptotic cell death only with d-Ser. Further research is required to gain a better understanding of the mechanisms underlying d-AA-induced inflammation and its downstream consequences, especially in the context of aging given the wide detection of these entities in systemic circulation. © The Author(s) 2024.
Keywords
Amino Acids, Cytokines, Humans, Hydrogen Peroxide, Interleukin-8, NF-kappa B, Tumor Necrosis Factor-alpha, alanine, dextro amino acid, hydrogen peroxide, immunoglobulin enhancer binding protein, interleukin 8, serine, tumor necrosis factor, amino acid, cytokine, immunoglobulin enhancer binding protein, interleukin 8, tumor necrosis factor, amino acid analysis, apoptosis assay, Article, caspase assay, cell death, controlled study, cytokine release, Hep-G2 cell line, human, human cell, in vitro study, mitochondrial membrane potential, mRNA expression level, protein expression, protein expression level, upregulation, chemistry, metabolism
Divisions
medicinedept,ceria,pharchemistry
Funders
Fundamental Research Grant Scheme,Ministry of Higher Education, Government of Malaysia,International Centre for Genetic Engineering and Biotechnology [CRP/MYS17-05],Agilent Technologies, Inc (PV018-2017) [FRGS/1/2019/SKK08/UM/02/7]
Publication Title
Amino Acids
Volume
56
Issue
1
Publisher
Springer
Additional Information
All Open Access, Hybrid Gold Open Access