Journal
MOLECULAR ENDOCRINOLOGY
Volume 19, Issue 1, Pages 113-124Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2004-0270
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Funding
- NINDS NIH HHS [NS-36765, NS-39954] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS039954, R01NS036765] Funding Source: NIH RePORTER
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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 (E-2) 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 E-2 inhibition of class II MHC expression suggests that E-2 is signaling in a nonclassical manner. We find that E-2, 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 E-2, TAM, and ICI on class II MHC expression. E-2, TAM, and ICI activate the JNK pathway and subsequently activate c-Jun and activating transcription factor-2 transcription factors. Our results demonstrate that blocking E-2 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 E-2-mediated inhibition of class II MHC expression.
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