Induction of interleukin 21 receptor expression via enhanced intracellular metabolism in B cells and its relevance to the disease activity in systemic lupus erythematosus.

Abstract

Objective: To elucidate the association between the changes in intracellular metabolism in the early stage of B cell activation and systemic lupus erythematosus (SLE) pathogenesis.

Methods: CD19⁺ or CD19⁺CD27^- (naïve) cells from the peripheral blood of healthy controls and lupus patients were cultured under different stimuli. The changes in intracellular metabolism and signalling pathways in these cells were evaluated.

Results: Stimulation with CpG (Toll-like receptor 9 (TLR9) ligand) in vitro induced enhanced interleukin 21 (IL-21) receptor expression in CD19⁺CD27^- cells after 24 hours. The addition of IL-21 to the CpG stimulation enhanced the extracellular acidification rate, which indicates glycolysis, within 30 min. IL-21 receptor (IL-21R) expression induced by CpG stimulation was selectively inhibited by 2-deoxy-D-glucose (hexokinase 2 (HK2) inhibitor) and heptelidic acid (glyceraldehyde 3-phosphate dehydrogenase (GAPDH) inhibitor). RNA immunoprecipitation with anti-GAPDH antibody revealed that CpG stimulation dissociated the binding between IL-21R messenger RNA (mRNA) and GAPDH under no stimulation. HK2 and GAPDH expression were higher in CD19⁺CD27^- cells of lupus patients than in those of healthy controls, and GAPDH expression was correlated with the plasmocyte count and disease activity score.

Conclusion: IL-21R mRNA-GAPDH binding dissociation associated with rapid glycolytic enhancement by the TLR9 ligand in B cells may induce plasmocyte differentiation through IL-21 signals and be involved in exacerbating SLE.