Thalidomide and its immune-modulating analogs alter the production of the inflammatory cytokines TNF-α, IL-1, IL-6, IL-12 and anti-inflammatory cytokine IL-10. The analogs are believed to inhibit the production of TNF-α, where the analogs are up to 50.000 times more potent in vitro than the parent drug thalidomide. The mechanism is believed to be through enhanced degradation of TNF-α mRNA, resulting in diminished amounts of this pro-inflammatory cytokine secreted. This explains the effect of thalidomide when given to ENL patients, as they commonly have high levels of TNF-α in their blood and in dermatological lesions. In contrast, in vitro assay demonstrated that TNF-α is actually enhanced in T-cell activation, where CD4+ and CD8+ T lymphocytes were stimulated by anti-CD3 which was later confirmed in an early phase trials involving solid tumors and inflammatory dermatologic diseases.
IL-12 is another cytokine both suppressed and enhanced by thalidomide and its analogs. When monocytes are stimulated by lipopolysaccharides, IL-12 production is suppressed but during T-cell stimulation the production is enhanced.
Lenalidomide is believed to be about 1000 times more potent in vitro than thalidomide in anti-inflammatory properties and pomalidomide about 10 times more potent than lenalidomide. It is worth noticing however that, when comparing lenalidomide and pomalidomide, clinical relevance of higher in vitro potency is unclear since maximum tolerated dose of pomalidomide is 2 mg daily compared to 25 mg for lenalidomide, leading to 10-100 times lower plasma drug concentration of pomalidomide.