Newly Synthesized Phosphodiesterase 4 (PDE4) Inhibitor, DWP205505, Inhibits TNF- $\alpha$ Secretion and mRNA Expression

The therapeutic potential of phosphodiesterase 4 (PDE4) inhibitors in inflammatory diseases including some autoimmune diseases has been explored recently with some hopeful results. These PDE4 inhibitors are thought to show their anti-inflammatory effect by down-regulating tumor necrosis factor-α (TNF-α) production in lymphocytes and macrophages. A high concentration of TNF-α has been found in rheumatoid arthritis (RA) synovium and reducing TNF-α using biological agents was proven to be an effective RA treatment. To test the possibility of using PDE4 inhibitors for RA treatment, the effects of a newly synthesized PDE4 inhibitor, DWP205505, on TNF-α and IL-10 production was tested in cells isolated from normal peripheral blood and rheumatoid arthritis synovial fluid. Cytokine production was assayed at the protein level by sandwich enzyme-linked immunosorbent assay (ELISA) and at the mRNA expression level by semi-quantitative RT-PCR. Another PDE4 inhibitor, RP73401, was used for comparison. DWP205505 and RP73401 had no harmful effect on cell viability up to 10 μM concentration during the 24 h culture period. DWP205505 as well as RP73401 significantly reduced TNF-α secretion from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC). The effect of DWP205505 or RP73401 treatment on the mRNA expression of TNF-α was also studied in LPS-stimulated PBMC and SFMC. TNF-α mRNA expression was increased by LPS stimulation and both of the PDE4 inhibitors suppressed TNF-α mRNA expression. For interleukin-10 (IL-10), a little different results were obtained from PBMC and SFMC; IL-10 secretion was unaffected by LPS stimulation and only minimally affected by both of the PDE4 inhibitors in PBMC. In unstimulated SFMC, DWP205505 and RP73401 slightly enhanced IL-10 secretion, while they reduced IL-10 secretion from LPS-stimulated SFMC where IL-10 secretion was a lot higher than unstimulated SFMC. These results suggest that the newly synthesized PDE4 inhibitor DWP205505 may have anti-rheumatoid arthritis activity.