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Submitted on July 5, 2004
Accepted on September 13, 2004
-Estradiol Activation of the c-Jun N-Terminal Kinase Pathway Leads to Down-Regulation of Class II MHC Expression
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294
* To whom correspondence should be addressed. 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 17-beta estradiol (E2) down-regulates class II MHC expression by attenuation of histone acetylation and CREB-binding protein (CBP) recruitment to the class II MHC promoter. Estrogen signals through nuclear receptors to mediate genomic effects, however, estrogen is also known to mediate rapid non-genomic effects. Our observation that ER antagonists fail to prevent E2 inhibition of class II MHC expression suggests that E2 is signaling in a non-classical manner. We find that E2, as well as the anti-estrogens tamoxifen (TAM) and ICI 182,780 (ICI), inhibit class II MHC expression through activation of the c-Jun N-terminal kinase (JNK) pathway. Pharmalogical 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 ATF-2 transcription factors. Our results demonstrate that blocking E2 activation of the JNK signaling pathway prevents estrogen mediated attenuation of histone acetylation and CBP 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.
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