Anti-inflammatory drugs and tumor necrosis factor-α production from monocytes: Role of transcription factor NF-κB and implication for rheumatoid arthritis therapy

Inhibition of tumor necrosis factor-α (TNF-α) represents a relevant target in rheumatoid arthritis therapy. Besides inhibiting cyclooxygenase, anti-inflammatory drugs can affect the activation of transcription factors. We investigated the ability of dexamethasone, indomethacin, and rofecoxib to modulate nuclear factor-κB (NF-κB) activation and TNF-α release from human monocytes challenged with lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA). Both stimuli induced NF-κB nuclear translocation and TNF-α secretion. Dexamethasone potently inhibited TNF-α release, indomethacin inhibited only PMA-evoked release, while rofecoxib had no effect. In the electrophoretic mobility shift assay, dexamethasone and rofecoxib dose-dependently inhibited the DNA binding activity of NF-κB in stimulated monocytes, whereas indomethacin failed to inhibit the LPS-evoked one. These results were further confirmed by evaluating the drugs' ability to reduce nuclear NF-κB subunits, as well as the amount of phosphorylated IκBα in cytosolic fractions. In conclusion, these results indicate that anti-inflammatory drugs differ largely in their ability to inhibit NF-κB activity and/or TNF-α release from human monocytes. These effects can be relevant to rheumatoid arthritis therapy.