Medroxyprogesterone acetate downregulates cytokine gene expression in mouse fibroblast cells.
Although medroxyprogesterone acetate (MPA) is used as an injectable contraceptive, in hormone replacement therapy (HRT) and in treatment of certain cancers, the steroid receptors and their target genes involved in the actions of MPA are not well understood. We show that MPA, like dexamethasone (dex), significantly represses tumour necrosis factor (TNF)-stimulated interleukin-6 (IL-6) protein production in mouse fibroblast (L929sA) cells. In addition, MPA repressed IL-6 and IL-8 promoter-reporter constructs at the transcriptional level, via interference with nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1). Furthermore, like dex, MPA does not affect NFkappaB DNA-binding activity. We also observed significant transactivation by MPA of a glucocorticoid response element (GRE)-driven promoter-reporter construct in both L929sA and COS-1 cells. The MPA-induced nuclear translocation of the glucocorticoid receptor (GR), as well as the antagonistic effects of RU486, strongly suggest that the actions of MPA in these cells are mediated at least in part via the GR.
Koubovec
Dominique
D
Department of Biochemistry, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa.
Vanden Berghe
Wim
W
Vermeulen
Linda
L
Haegeman
Guy
G
Hapgood
Janet Patricia
JP
D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000235:genetics / Q000502:physiology; D020218:Response Elements / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000378:metabolism
D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D003907:Dexamethasone; D017258:Medroxyprogesterone Acetate