How Synergistically Inhibiting the Nuclear Factor-Kappa B (NF-κB) and Hypoxia-Inducible Factor-1α (HIF-1α) Pathways Can Lead to Better Outcomes in Patients with Rheumatoid Arthritis
Marcus Stepney
Background: Rheumatoid arthritis is an inflammatory disease that affects millions of patients worldwide 1. Patients suffering from Rheumatoid arthritis (RA) tend to present with joint pain and swelling from the inflammation produced from macrophages that release proinflammatory cytokines such as IL-1β and TNF-α.1,2 The proinflammatory pathway nuclear factor-kappa B (NF-κB), is known to play a pivotal part in the inflammation and immune response seen in patients with RA.3 Dexamethasone, is a synthetic glucocorticoid that is used in treating patients suffering from RA and is known to inhibit the NF-Κb.4 The effect of synergistically inhibiting other inflammatory pathways has on inflammation is an area of research that is still ongoing.
Objective: In this experiment, researchers examined the impact on reducing inflammation by combining Dexamethasone with Artesunate, a known inhibitor of hypoxia-inducible factor-1α (HIF-1α)4.
Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the key terms: “Rheumatoid Arthritis” and “Nuclear factor-kappa B (NF-κB)”
Results: When Dexamethasone was combined with Artesunate in a reactive oxygen species micelle (DEX/HTA), it showed the greatest inhibition of NF-κB p65, HIF-1α, and IκB-α levels in mouse bone marrow-derived macrophages compared to all other groups.4 Mouse bone marrow-derived macrophages showed the greatest shift towards M2 anti-inflammatory macrophages in the (DEX/HTA) group.4 The (DEX/HTA) group showed the greatest decrease in the pro-inflammatory markers of IL-1β and TNF-α in bone-marrow derived macrophages.4 DEX/HTA group showed the greatest decrease in paw swelling among the various groups at the end point of therapy in the inflamed joints of adjuvant induced arthritis rat models. The paw sizes of rats treated with DEX/HTA returned to nearly normal levels of swelling.4
Conclusion: The study has shown the reactive oxygen species (DEX/HTA) group which synergistically inhibited both the nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α) pathways had the greatest effect of inhibiting NF-κB p65, HIF-1α. The (DEX/HTA) group also showed to have the greatest reduction in swelling in the joints of adjuvant induced rat models. This data suggests that synergistically inhibiting both the NF-Κb and HIF-1α leads to better outcomes than therapies that solely target NF-Κb or HIF-1α pathways. The raw data used to reproduce these results was not released because of its use in an ongoing study.
Work Cited:
- Chauhan K, Jandu JS, Al-Dhahir MA. Rheumatoid Arthritis. PubMed. Published 2023. https://www.ncbi.nlm.nih.gov/books/NBK441999/
- Roszkowski L, Ciechomska M. Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis. Cells. 2021;10(8):1860. Published 2021 Jul 22. doi:10.3390/cells10081860
- Peng C, Ouyang Y, Lu N, Li N. The NF-κB Signaling Pathway, the Microbiota, and Gastrointestinal Tumorigenesis: Recent Advances. Front Immunol. 2020;11:1387. Published 2020 Jun 30. doi:10.3389/fimmu.2020.01387
- Li Y, Liang Q, Zhou L, et al. An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization. Acta Biomater. 2022;152:406-424. doi:10.1016/j.actbio.2022.08.054