17beta-estradiol activation of the c-Jun N-terminal kinase pathway leads to down-regulation of class II major histocompatibility complex expression.
Class II major histocompatibility complex (MHC) proteins are important for specific recognition of foreign antigens by the immune system. Previously we showed that 17beta-estradiol (E2) down-regulates class II MHC expression by attenuation of histone acetylation and cAMP response element binding protein (CREB)-binding protein recruitment to the class II MHC promoter. Estrogen signals through nuclear receptors to mediate genomic effects; however, estrogen is also known to mediate rapid nongenomic effects. Our observation that ER antagonists fail to prevent E2 inhibition of class II MHC expression suggests that E2 is signaling in a nonclassical manner. We find that E2, as well as the antiestrogens tamoxifen (TAM) and ICI 182,780 (ICI), inhibit class II MHC expression through activation of the c-Jun N-terminal kinase (JNK) pathway. Pharmacological JNK inhibitors reverse the inhibitory effects of E2, TAM, and ICI on class II MHC expression. E2, TAM, and ICI activate the JNK pathway and subsequently activate c-Jun and activating transcription factor-2 transcription factors. Our results demonstrate that blocking E2 activation of the JNK signaling pathway prevents estrogen-mediated attenuation of histone acetylation and CREB-binding protein recruitment to the class II MHC promoter. Collectively, these findings demonstrate that the JNK signaling pathway is necessary for E2-mediated inhibition of class II MHC expression.
Adamski
Jill
J
Department of Cell Biology, University of Alabama at Birmingham, 1530 3rd Avenue, South, McCallum 395, Birmingham, Alabama 35294-0005, USA.
Benveniste
Etty N
EN
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D006657:Histones; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D013629:Tamoxifen; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases