Differential effects of RU486 reveal distinct mechanisms for glucocorticoid repression of prostaglandin E2 release

被引:44
作者
Chivers, JE
Cambridge, LM
Catley, MC
Mak, JC
Donnelly, LE
Barnes, PJ
Newton, R [1 ]
机构
[1] Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England
[2] Univ London Imperial Coll Sci Technol & Med, Fac Med, Natl Heart & Lung Inst, Dept Thorac Med, London, England
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 2004年 / 271卷 / 20期
关键词
corticosteroid; cyclooxygenase; epithelial cell; glucocorticoid receptor; prostaglandin E2;
D O I
10.1111/j.1432-1033.2004.04342.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In A549 pulmonary cells, the dexamethasone- and budesonide-dependent repression of interleukin-1beta-induced prostaglandin E-2 release was mimicked by the steroid antagonist, RU486. Conversely, whereas dexamethasone and budesonide were highly effective inhibitors of interleukin-1beta-induced cyclooxygenase (COX)/prostaglandin E synthase (PGES) activity and COX-2 expression, RU486 (< 1 mum) was a poor inhibitor, but was able to efficiently antagonize the effects of dexamethasone and budesonide. In addition, both dexamethasone and RU486 repressed [H-3]arachidonate release, which is consistent with an effect at the level of phospholipase A(2) activity. By contrast, glucocorticoid response element-dependent transcription was unaffected by RU486 but induced by dexamethasone and budesonide, whilst dexamethasone- and budesonide-dependent repression of nuclear factor-kappaB-dependent transcription was maximally 30-40% and RU486 (< 1 mum) was without significant effect. Thus, two pharmacologically distinct mechanisms of glucocorticoid-dependent repression of prostaglandin E-2 release are revealed. First, glucocorticoid-dependent repression of arachidonic acid is mimicked by RU486 and, second, repression of COX/PGES is antagonized by RU486. Finally, whilst all compounds induced glucocorticoid receptor translocation, no role for glucocorticoid response element-dependent transcription is supported in these inhibitory processes and only a limited role for glucocorticoid-dependent inhibition of nuclear factor-kappaB in the repression of COX-2 is indicated.
引用
收藏
页码:4042 / 4052
页数:11
相关论文
共 47 条
[1]   Therapeutic strategies for allergic diseases [J].
Barnes, PJ .
NATURE, 1999, 402 (6760) :B31-B38
[2]   INTRAGENIC SEQUENCES OF THE HUMAN GLUCOCORTICOID RECEPTOR COMPLEMENTARY-DNA MEDIATE HORMONE-INDUCIBLE RECEPTOR MESSENGER-RNA DOWN-REGULATION THROUGH MULTIPLE MECHANISMS [J].
BURNSTEIN, KL ;
JEWELL, CM ;
SAR, M ;
CIDLOWSKI, JA .
MOLECULAR ENDOCRINOLOGY, 1994, 8 (12) :1764-1773
[3]   Inhibitors of protein kinase C (PKC) prevent activated transcription -: Role of events downstream of NF-κB DNA binding [J].
Catley, MC ;
Cambridge, LM ;
Nasuhara, Y ;
Ito, K ;
Chivers, JE ;
Beaton, A ;
Holden, NS ;
Bergmann, MW ;
Barnes, PJ ;
Newton, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (18) :18457-18466
[4]   IL-1β-dependent activation of NF-κB mediates PGE2 release via the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase [J].
Catley, MC ;
Chivers, JE ;
Cambridge, LM ;
Holden, N ;
Slater, DM ;
Staples, KJ ;
Bergmann, MW ;
Loser, P ;
Barnes, PJ ;
Newton, R .
FEBS LETTERS, 2003, 547 (1-3) :75-79
[5]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[6]   Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism [J].
Croxtall, JD ;
Choudhary, Q ;
Flower, RJ .
BRITISH JOURNAL OF PHARMACOLOGY, 2000, 130 (02) :289-298
[7]   Differential modulation of glucocorticoid action by FK506 in A549 cells [J].
Croxtall, JD ;
Paul-Clark, M ;
van Hal, PTW .
BIOCHEMICAL JOURNAL, 2003, 376 :285-290
[8]   A subset of kappa opioid ligands bind to the membrane glucocorticoid receptor in an amphibian brain [J].
Evans, SJ ;
Searcy, BT ;
Moore, FL .
ENDOCRINOLOGY, 2000, 141 (07) :2294-2300
[9]   Partial purification and biochemical characterization of a membrane glucocorticoid receptor from an amphibian brain [J].
Evans, SJ ;
Murray, TF ;
Moore, FL .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2000, 72 (05) :209-221
[10]   Selective activation of the glucocorticoid receptor by steroid antagonists in human breast cancer and osteosarcoma cells [J].
Fryer, CJ ;
Kinyamu, HK ;
Rogatsky, I ;
Garabedian, MJ ;
Archer, TK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (23) :17771-17777