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Estrogen plays a critical regulatory role in the development and maintenance of immunity. Its role in the regulation of antibody synthesis in vivo is still not completely clear. Here, we have compared the effect of estrogen on T cell-dependent (TD) and T cell-independent type 2 (TI-2) antibody responses. The results provide the first evidence that estrogen enhances the TD but not the TI-2 response. Ovariectomy significantly decreased, while estrogen re-administration increased the number of hapten-specific IgM- and IgG-producing cells in response to TD antigen. In vitro experiments also show that estrogen may have a direct impact on B and T cells by inducing rapid signaling events, such as Erk and AKT phosphorylation, cell-specific Ca(2+) signal, and NFkappaB activation. These non-transcriptional effects are mediated by classical estrogen receptors and partly by an as yet unidentified plasma membrane estrogen receptor. Such receptor- mediated rapid signals may modulate the in vivo T cell-dependent immune response.

Rapid, nonclassical 17β-estradiol (E2) actions are thought to play an important role in the modulation of neuronal function. The present study addresses the intracellular signaling cascades involved in the rapid E2-induced phosphorylation of cAMP response element binding protein (CREB) in GnRH neurons. Administration of E2 to adult female mice resulted in the activation of ERK1/2 in GnRH neurons within 15 min. In vitro studies using pharmacological antagonists showed that ERK1/2 was essential for E2-induced CREB phosphorylation in GnRH neurons. Upstream to this, protein kinase A and calcium/calmodulin-dependent protein kinase type II, but not protein kinase C, were found to be necessary for E2-induced phosphorylation of ERK1/2. This rapid E2 signaling cascade in GnRH neurons was found to require both direct and indirect E2 actions. E2 failed to phosphorylate ERK1/2 and CREB in GnRH neuron-specific estrogen receptor β knockout mice in vivo. Equally, however, a cocktail of tetrodotoxin and γ-aminobutyric acid(A)/glutamate receptor antagonists also blocked E2-induced ERK1/2 phosphorylation in GnRH neurons in wild-type mice in vitro. Together, these observations indicate that E2 acts through calcium/calmodulin-dependent protein kinase type II and protein kinase A to rapidly phosphorylate ERK1/2, which then acts to phosphorylate CREB in adult female GnRH neurons. Intriguingly, these effects of E2 are dependent upon both direct ERβ mechanisms as well as indirect actions mediated by afferent inputs to GnRH neurons.