Hypoxia‐inducible factor‐1α regulates the interleukin‐6 production by B cells in rheumatoid arthritis

Abstract

Objectives Rheumatoid arthritis (RA) is a disease characterised by bone destruction and systemic inflammation, and interleukin‐6 (IL‐6) is a therapeutic target for treating it. The study aimed at investigating the sources of IL‐6 and the influence of hypoxia‐inducible factor‐1α (HIF‐1α) on IL‐6 production by B cells in RA patients. Methods The phenotype of IL‐6‐producing cells in the peripheral blood of RA patients was analysed using flow cytometry. Bioinformatics, real‐time polymerase chain reaction, Western blot and immunofluorescence staining were used to determine the IL‐6 production and HIF‐1α levels in B cells. A dual‐luciferase reporter assay and chromatin immunoprecipitation were used to investigate the regulatory role of HIF‐1α on IL‐6 production in human and mouse B cells. Results Our findings revealed that B cells are major sources of IL‐6 in the peripheral blood of RA patients, with the proportion of IL‐6‐producing B cells significantly correlated with RA disease activity. The CD27 − IgD + naïve B cell subset was identified as the typical IL‐6‐producing subset in RA patients. Both HIF‐1α and IL‐6 were co‐expressed by B cells in the peripheral blood and synovium of RA patients, and HIF‐1α was found to directly bind to the IL6 promoter and enhance its transcription. Conclusion This study highlights the role of B cells in producing IL‐6 and the regulation of this production by HIF‐1α in patients with RA. Targeting HIF‐1α might provide a new therapeutic strategy for treating RA.

Hypoxia-Inducible Factor and Oxidative Stress in Tendon Degeneration: A Molecular Perspective

“…Activated NF-κB further promotes HIF-1 levels, thereby enhancing HIF-1-mediated activity [145]. HIF-1, in turn, promotes the expression of NF-κB target genes, such as COX-2 [146] and IL-6 [147], resulting in a prolonged state of inflammation and delayed healing [105].…”

The Application of Drugs and Nano-Therapies Targeting Immune Cells in Hypoxic Inflammation

“…It binds to their promoters, augmenting their transcription. 77,78 In patients with Rheumatoid Arthritis (RA), B cells are the primary source of IL-6 in peripheral blood and are closely associated with RA disease activity. 77 The production of IL-10, which modulates the differentiation of innate-like B cells and B10 cells, leads to reduced IgM 76 IL-10 is known to mitigate inflammation; conversely, IL-10-knockout mice have displayed chronic inflammation.…”

“…77,78 In patients with Rheumatoid Arthritis (RA), B cells are the primary source of IL-6 in peripheral blood and are closely associated with RA disease activity. 77 The production of IL-10, which modulates the differentiation of innate-like B cells and B10 cells, leads to reduced IgM 76 IL-10 is known to mitigate inflammation; conversely, IL-10-knockout mice have displayed chronic inflammation. 79 Furthermore, the expression of hCXCR4 is vital in regulating B cell viability under hypoxia, influenced by hypoxia-induced ROS, HIF-1α, and Nrf2.…”