Mitigating LPS-Induced Inflammation in AGS Cells via the TLR4 Pathway with Fumaric Acids

Document Type : Original Article

Authors

1 Department of Biology, Faculty of Science, University of Zanjan, Zanjan, Iran.

2 Department of Biotechnology, Research Institute of Modern Biological Techniques, University of Zanjan, Zanjan, Iran.

3 Department of Biotechnology, Research Institute of modern biological techniques, university of Zanjan, Zanjan, Iran.

Abstract

The study investigates the effects of fumaric acid on Toll-like receptor (TLR) expression, cytokine production, and cell viability in AGS cells exposed to lipopolysaccharide (LPS), a potent inducer of inflammation. TLRs play a key role in the innate immune system, responding to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) by producing pro-inflammatory cytokines. Fumaric acid, present in fruits and vegetables, is known for its anti-inflammatory and potential anti-cancer properties.Results indicate that LPS boosts TLR expression and the production of pro-inflammatory cytokines (IL-1β and TNF-alpha) in AGS cells. Fumaric acid, especially at higher doses, moderates cytokine expression. Gene expression analysis suggests fumaric acid may alleviate inflammation by affecting cytokine production, possibly aiding cancer treatment.Annexin PI assay shows fumaric acid's independent impact on AGS cell viability; in combination with LPS, it significantly alters cell death, implying synergistic interaction. MTT assay further confirms fumaric acid's positive effect on AGS cell survival against LPS-induced damage.The discussion highlights fumaric acid's known anti-inflammatory and anti-cancer effects. This study adds insights into its impact on cytokine production and safeguarding cells from LPS damage. The differing effects on viability and death when fumaric acid and LPS are combined require further exploration considering factors like cell type, dose, and exposure time. To conclude, this research underscores fumaric acid's therapeutic potential against inflammation and cancer. It reveals its influence on TLR signaling, cytokine production, and cell viability in AGS cells exposed to LPS. Nevertheless, more research is needed to fully understand its mechanisms and clinical uses.

Keywords

Main Subjects

References

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Mogensen, T.H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clinical Microbiology Reviews, 2009, 22(2), 240–273.
Li, D., & Wu, M. Pattern recognition receptors in health and diseases. Signal Transduction and Targeted Therapy, 2021, 6(1), 291.
Park, B.S., et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature, 2009, 458(7242), 1191–1195.
Hajjar, A.M., et al. Human Toll-like receptor 4 recognizes host-specific LPS modifications. Nature Immunology, 2002, 3(4), 354–359.
O'Neill, L.A.J., & Bowie, A.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Reviews Immunology, 2007, 7(5), 353–364.
Zhao, H., et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduction and Targeted Therapy, 2021, 6(1), 263.
Li, H., Wu, M., & Zhao, X. Role of chemokine systems in cancer and inflammatory diseases. MedComm (2020), 2022, 3(2), e147.
Ramirez-Ortiz, Z.G., & Means, T.K. The role of dendritic cells in the innate recognition of pathogenic fungi (A. fumigatus, C. neoformans and C. albicans). Virulence, 2012, 3(7), 635–646.
Romerio, A., & Peri, F. Increasing the chemical variety of small-molecule-based TLR4 modulators: an overview. Frontiers in Immunology, 2020, 11, 1210.
Owen, A.M., et al. TLR agonists as mediators of trained immunity: mechanistic insight and immunotherapeutic potential to combat infection. Frontiers in Immunology, 2020, 11, 622614.
Heine, H., & Zamyatina, A. Therapeutic targeting of TLR4 for inflammation, infection, and cancer: a perspective for disaccharide lipid A mimetics. Pharmaceuticals, 2023, 16(1), 23.
Sostres, C., Gargallo, C.J., & Lanas, A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Research & Therapy, 2013, 15(Suppl 3), S3.
Bindu, S., Mazumder, S., & Bandyopadhyay, U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochemical Pharmacology, 2020, 180, 114147.
Chen, C.Y. TCM Database@Taiwan: the world's largest traditional Chinese medicine database for drug screening in silico. PLoS One, 2011, 6(1), e15939.
Heidari, F., et al. Fumaric acids as a novel antagonist of TLR-4 pathway mitigates arsenic-exposed inflammation in human monocyte-derived dendritic cells. Immunopharmacology and Immunotoxicology, 2019, 41(4), 513–520
Journal of Epigenetics
Volume 6, Issue 1
June 2025
Pages 17-30

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History

  • Receive Date: 31 December 2024
  • Revise Date: 11 January 2025
  • Accept Date: 27 January 2025

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