TITLE:
Effects of structural modification of anti-inflammatory steroidal antedrug on pro-inflammatory mediators and inhibitory cytokines in human alveolar epithelial cells
AUTHORS:
Gui-Fang Wang, Soonjo Kwon, Rakesh Sharma, Hemang Patel, Henry J. Lee
KEYWORDS:
Steroidal Antedrug; NO Production; IL-8 Production; Anti-Inflammatory Cytokine Receptor; IL-22 Receptor
JOURNAL NAME:
Health,
Vol.1 No.3,
December
1,
2009
ABSTRACT: The anti-inflammatory effects of the new ster-oidal antedrug, 21-acetyloxy-9α-fluoro-11β-hy-droxyl-3, 20-dioxo-1, 4-pregnadieno-[16α, 17α-d] isoxazoline (FP-ISO-21AC), on nitric oxide (NO) and interleukin 8 (IL-8) production, were inves-tigated together with its parent steroid predni-solone (PRED). PRED is one of the anti-in-flammatory steroids but has systemic side ef-fects which limit the use of it. PRED was modi-fied with ‘antedrug concept’ to create safer drugs that attack problems such as inflamma-tion, then quickly become inactive before they can cause systemic side effect. We had a test about the effect of the modified anti-inflamma-tory steroidal antedrug on anti-inflammatory activity. The present study evaluated their ability to inhibit cytokine-induced NO and IL-8 produc-tion in human alveolar epithelial cells. We also investigated their ability to enhance the expres-sion of inhibitory cytokine receptor, interleukin 22 receptor (IL-22R) in human alveolar epithelial cells. Our results showed that FP-ISO-21AC sh- owed higher ability to inhibit the cytokine - in-duced 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 ex-ogenous inhibitory cytokine IL-22, further re-duction 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 en-hanced the expression of IL-22R. FP-ISO- 21AC 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 con-clusion, a synthesized steroidal antedrug FP- ISO-21AC showed higher anti-inflammatory ef-fects than PRED by inhibiting the expression of pro-inflammatory mediator NO and stimulating the expression of IL-22R.