The nuclear factor kappa-light-chain-enhancer of the activated B-cell nuclear translocation (NF-κB) signaling pathway partly mediates interleukin-6 (IL-6) production in neuromyelitis optica spectrum disorder (NMOSD), according to an article published in Neuroscience.
Researchers also found that the NF-κB inhibitor, S3633, was able to halt the release of IL-6, indicating that NF-κB may be a potentially effective therapeutic target.
In the study, levels of IL-6, which may play multiple roles in the pathophysiology of NMOSD, were found to be significantly elevated in patients with NMOSD compared to those in healthy controls. When neuromyelitis optica immunoglobulin G (NMO-IgG) was taken from patients with NMOSD and incubated with primary rat astrocytes, it stimulated the production of IL-6.
In addition, incubation with NMO-IgG caused the NF-κB protein to enter the nuclei of the astrocytes and led to a significant increase in the amount of phosphorylated NF-κB inside the cells. NMO-IgG treatment also resulted in the internalization of aquaporin-4 (AQP4) proteins in the astrocytes.
Treatment with S3633 1 hour before stimulation with NMO-IgG significantly reduced the release of IL-6 protein and the creation of IL-6 messenger RNA (mRNA) in astrocytes, however. Incubating the astrocytes with a Janus kinase (JAK)-specific inhibitor, AZD1480, also resulted in a decrease in IL-6 protein and mRNA levels, both on its own and in conjunction with S3633.
Read more about NMOSD pathophysiology
“Here, we found that S3633, an inhibitor of the NF-κB pathway, significantly reduced the release of IL-6 from astrocytes stimulated with NMO-IgG, indicating that NF-κB-related signaling pathways play an important role in NMO-IgG-induced IL-6 production in astrocytes,” the study authors said.
NF-κB has been well studied in other literature and is involved in autoimmunity through the regulation of inflammation and immune tolerance. Previous research has also shown the NF-κB pathway to be involved in the pathogenesis of several other autoimmune diseases.
In the clinical portion of the study, sera from 59 NMOSD patients and 21 healthy controls were collected and analyzed. No significant differences in age or sex were observed between the 2 groups.
Wang Y, Zhang J, Chang H, et al. NMO-IgG induce interleukin-6 release via activation of the NF-κB signaling pathway in astrocytes. Neuroscience. Published online June 3, 2022. doi:10.1016/j.neuroscience.2022.05.038