Effects of structural modification of anti-inflammatory steroidal antedrug on pro-inflammatory mediators and inhibitory cytokines in human alveolar epithelial cells

The anti-inflammatory effects of the new steroidal antedrug, 21-acetyloxy-9α-fluoro-11β-hydroxyl-3, 20-dioxo-1, 4-pregnadieno-[16α, 17α-d] isoxazoline (FP-ISO-21AC), on nitric oxide (NO) and interleukin 8 (IL-8) production, were investigated together with its parent steroid prednisolone (PRED). PRED is one of the anti-inflammatory steroids but has systemic side effects which limit the use of it. PRED was modified with ‘antedrug concept’ to create safer drugs that attack problems such as inflammation, then quickly become inactive before they can cause systemic side effect. We had a test about the effect of the modified anti-inflammatory steroidal antedrug on anti-inflammatory activity. The present study evaluated their ability to inhibit cytokine-induced NO and IL-8 production in human alveolar epithelial cells. We also investigated their ability to enhance the expression of inhibitory cytokine receptor, interleukin 22 receptor (IL-22R) in human alveolar epithelial cells. Our results showed that FP-ISO-21AC showed higher ability to inhibit the cytokine induced production of NO than PRED. Exogenous IL-22 was added to the media of both human alveolar epithelial cells (A549) and human lung fibroblast (HLF-1). In the presence of the exogenous inhibitory cytokine IL-22, further reduction of NO production was observed in A549 cells, which express IL-22R, but not in HLF1, which does not express IL-22R. These data suggested that the steroidal antedrugs enhanced the expression of IL-22R. FP-ISO21AC showed higher potency than PRED to restore the expression of IL-22R. FP-ISO-21AC further reduced NO production to 27% and PRED further reduced NO production to 39%. In conclusion, a synthesized steroidal antedrug FPISO-21AC showed higher anti-inflammatory effects than PRED by inhibiting the expression of pro-inflammatory mediator NO and stimulating the expression of IL-22R.