| Class II major histocompatibility complex (MHC) proteins are important for the initiation of immune responses and are essential for specific recognition of foreign antigens by the immune system. The class II transactivator protein is the master regulator that is essential for both constitutive and interferon-gamma-inducible class II MHC expression. Estrogen [17beta-estradiol (E2)] and other estrogenic compounds have been shown to have immunomodulatory effects. In this study, I examine a novel mechanism utilized by estrogenic compounds to down-regulate class II MHC expression.; First, I demonstrate that E2 down-regulates class II MHC protein levels on multiple cell types. Surprisingly, the inhibitory effects of E 2 on class II MHC expression are not due to changes in class II transactivator expression; rather, E2 mediates inhibition at the level of class II MHC gene expression. I find that E2 attenuates H3 and H4 histone acetylation and cAMP response element binding protein-binding protein association with the class II MHC promoter, suggesting that E2 inhibits class II MHC expression by a novel mechanism involving modification of the histone acetylation status of the promoter.; My observation that estrogen receptor antagonists fail to prevent E 2 inhibition of class II MHC expression suggests that E2 is signaling in a nonclassical manner. I find that E2 and the antiestrogens tamoxifen and ICI 182,780 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, tamoxifen and ICI 182,780 on class II MHC expression. E2, tamoxifen and ICI 182,780 activate the JNK pathway and subsequently activate c-Jun and activating transcription factor-2 transcription factors.; Finally, I demonstrate that blocking E2 activation of the JNK-signaling pathway prevents estrogen-mediated attenuation of histone acetylation and cAMP response element binding protein-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. In this study, I present a novel mechanism of class II MHC regulation by estrogenic compounds; this mechanism may help explain pregnancy-induced remission of some autoimmune diseases and could potentially lead to new therapeutic approaches towards treatment of these diseases. |
