Metabolic changes in synovial cells in early inflammation: Involvement of CREB phosphorylation in the anti-inflammatory effect of 2-deoxyglucose.

The involvement of metabolic reprogramming has been suggested to contribute to the pathophysiology of rheumatoid arthritis (RA). Glycolysis is enhanced in synovial cell metabolism in RA patients. Inhibitors of glycolysis are known to have anti-inflammatory effects. But, changes in the metabolism of normal synovial membranes or synovial cells during the early stages of inflammation remains unknown. Moreover, there are still many aspects of inflammatory signaling pathways altered by glycolysis inhibitors, that remain unclear. In this study we found that, in normal, non-pathological bovine synovial cells, most of ATP synthesis was generated by mitochondrial respiration. However, during the early of stages inflammation, initiated by lipopolysaccharide (LPS) exposure, synovial cells shifted to glycolysis for ATP production. The glycolysis inhibitor 2-deoxyglucose (2DG) reversed LPS induced increases in glycolysis for ATP production and suppressed the expression of inflammatory cytokines and proteolytic enzymes. 2DG suppressed the phosphorylation of the transcription factor cAMP response element binding protein (CREB) enhanced by LPS. Treatment with a CREB inhibitor reversed the expression of LPS-stimulated inflammatory cytokines and proteolytic enzymes. This study showed that changes in metabolism occur during the early stages of inflammation of synovial cells and can be reversed by 2DG and signaling pathways associated with CREB phosphorylation.