| Autor: |
Calderón E; Department of Internal Medicine, University of South Florida, College of Medicine 33612-4745., Gómez-Sánchez CE, Cozza EN, Zhou M, Coffey RG, Lockey RF, Prockop LD, Szentivanyi A |
| Jazyk: |
angličtina |
| Zdroj: |
Biochemical pharmacology [Biochem Pharmacol] 1994 Nov 29; Vol. 48 (11), pp. 2065-71. |
| DOI: |
10.1016/0006-2952(94)90506-1 |
| Abstrakt: |
Endothelin-1 (ET-1) is one of the most potent bronchoconstrictor agents yet described. Bronchial epithelial cells of asthmatic patients in vivo express preproET-1 and in vitro release high amounts of ET-1. Healthy and chronic bronchitic controls do not express preproET-1 or release ET-1. Interleukin-2 (IL-2) and other cytokines up-regulate the in vitro ET-1 release in guinea pig airway epithelial cells. We explored whether two glucocorticoids, dexamethasone (Dex) and triamcinolone acetonide (TA), inhibit the synthesis and release of ET-1 by A549 cells, a transformed human pulmonary epithelial cell line, since ET-1 may have a basic role in the pathogenesis of asthma. Cells were grown to confluence in RPMI 1640 plus 10% fetal bovine serum (FBS). Cells were then cultured for 3 days without serum to obtain ET-1 basal levels. The effects of 10% FBS, IL-2 (10 U/mL), Dex, TA or mifepristone, a steroid antagonist (1, 10 or 100 nM), were evaluated on ET-1 as measured by radioimmunoassay (RIA). ET-1 production increased from 57.6 +/- 5 pg/mg cell protein at 6 hr to 170 +/- 9 pg/mg cell protein at 72 hr in control cultures. Ten percent FBS increased ET-1 production from 58.7 +/- 9.6 to 399 +/- 14.5 pg/mg cell protein. IL-2 significantly increased ET-1 from 100.7 +/- 6.1 to 144 +/- 6.7 at 24 hr and from 170 +/- 9 to 207.7 +/- 24 at 72 hr. Dex and TA (10 and 100 nM) at 24-72 hr decreased ET-1 under basal conditions. Both drugs (only at 100 nM) decreased ET-1 production in 10% FBS- and IL-2-stimulated cells. Mifepristone (10 and 100 nM) reversed the decreased production of ET-1 induced by Dex (100 nM) at 24-72 hr. Northern blot analysis showed that Dex (100 nM) decreased the expression of ET-1 mRNA at 6 and 24 hr, but that mifepristone (100 nM) reversed this effect in cells cultured with Dex. In conclusion, Dex and TA down-regulate the synthesis and production of ET-1 by this human pulmonary epithelial cell line under basal or stimulated conditions, and these effects are reversed by mifepristone. These findings suggest a novel mechanism of glucocorticoid effect during the treatment of asthma. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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