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17ß-Estradiol Activation of the c-Jun N-Terminal Kinase Pathway Leads to Down-Regulation of Class II Major Histocompatibility Complex Expression

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294

Address all correspondence and requests for reprints to: Dr. Etty N. Benveniste, Department of Cell Biology, University of Alabama at Birmingham, 1530 3rd Avenue, South, McCallum 395, Birmingham, Alabama 35294-0005. E-mail: tika{at}uab.edu.

Class II major histocompatibility complex (MHC) proteins are important for specific recognition of foreign antigens by the immune system. Previously we showed that 17ß-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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Coregulators:   CBP

Ligands:   17β-Estradiol

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