Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions.

The CREB transcription factor regulates differentiation, survival, and synaptic plasticity. The complement of CREB targets responsible for these responses has not been identified, however. We developed a novel approach to identify CREB targets, termed serial analysis of chromatin occupancy (SACO), by combining chromatin immunoprecipitation (ChIP) with a modification of SAGE.

Estrogen treatment induces a novel population of regulatory cells, which suppresses experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a debilitating neurological disease characterized by a progressive loss of motor and sensory function, eventually leading to paralysis and death. The primary cause of neurological impairment is demyelination of the central nervous system (CNS) caused by an inflammatory autoimmune response. Previous studies have shown that the severity of MS is reduced during pregnancy, suggesting that the increased level of sex hormones may reduce the autoimmune response.

Mitogen- and stress-activated protein kinase 1 mediates cAMP response element-binding protein phosphorylation and activation by neurotrophins.

Activation of the transcription factor cAMP response element-binding protein (CREB) by neurotrophins is believed to regulate the survival, differentiation, and maturation of neurons in the CNS and PNS. Although phosphorylation of Ser133 is critical for the expression of CREB-regulated genes, the identity of neurotrophin-regulated Ser133 kinases has remained controversial. We show here that neurotrophin-induced CREB phosphorylation in CNS neurons depends exclusively on the extracellular signal-regulated kinase 1/2-activated kinase mitogen- and stress-activated protein kinase 1 (MSK1).

Opposing roles for TGF-beta1 and TGF-beta3 isoforms in experimental autoimmune encephalomyelitis.

Hormones can exert significant protective effects on autoimmune diseases by activating immunoregulatory mechanisms. One of the possible mechanisms of hormonal protection might be through the anti-inflammatory effects of the TGF-beta molecule. The present study investigated the changes in expression of two TGF-beta isoforms, TGF-beta1 and TGF-beta3, in C57BL/6 and TCR transgenic (T/R+) B10.

CNS gene expression pattern associated with spontaneous experimental autoimmune encephalomyelitis.

Transgenic mice with T-cell receptor (TCR) specific for myelin basic protein (MBP)-Ac1-11 peptide and homozygous for the RAG-1 mutation (T/R- mice) spontaneously develop acute progressive experimental autoimmune encephalomyelitis (Sp-EAE) mediated by CD4+ T cells. Microarray analysis of spinal cord tissue obtained from symptomatic versus non-symptomatic T/R- mice revealed strongly upregulated transcripts for genes involved in antigen presentation and processing, signal transduction, transcription regulation, metabolism, development, cell cycle, and many other processes involved in the induction of clinical and pathological signs of Sp-EAE. Several highly expressed genes were related directly to inflammation, including cytokines/receptors, chemokines/receptors, acute phase, complement molecules, and others.

17Beta-estradiol treatment profoundly down-regulates gene expression in spinal cord tissue in mice protected from experimental autoimmune encephalomyelitis.

It is now well documented that experimental autoimmune encephalomyelitis (EAE) can be effectively prevented by estrogen therapy. Previously, we identified a limited set of genes that were altered in spleens of mice protected from EAE by 17beta-estradiol (E2) treatment. As a continuation of these studies, we present here transcriptional changes in genes expressed in spinal cord tissue.

Transfer of severe experimental autoimmune encephalomyelitis by IL-12- and IL-18-potentiated T cells is estrogen sensitive.

The aim of this study was to evaluate the roles of IL-18 and IL-12 in potentiating the encephalitogenic activity of T cell lines specific for myelin oligodendrocyte glycoprotein (MOG(35-55)). MOG-specific T cells stimulated with anti-CD3 and anti-CD28 in the presence of IL-12 or IL-18 alone transferred only mild experimental autoimmune encephalomyelitis (EAE) into a low percentage of recipients. However, T cells cocultured with both cytokines transferred aggressive clinical and histological EAE into all recipients.

Endogenous CD4+BV8S2- T cells from TG BV8S2+ donors confer complete protection against spontaneous experimental encephalomyelitis (Sp-EAE) in TCR transgenic, RAG-/- mice.

To investigate regulatory mechanisms which naturally prevent autoimmune diseases, we adopted the genetically restricted immunodeficient (RAG-1(-/-)) myelin basic protein (MBP)-specific T cell receptor (TCR) double transgenic (T/R-) mouse model of spontaneous experimental autoimmune encephalomyelitis (Sp-EAE). Sp-EAE can be prevented after transfer of CD4+splenocytes from naïve immunocompetent mice. RAG-1+ double transgenic (T/R+) mice do not develop Sp-EAE due to the presence of a very small population (about 2%) of non-Tg TCR specificities.

Estrogen inhibition of EAE involves effects on dendritic cell function.

Estrogen has been found to have suppressive effects on the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. We have investigated the effects of 17beta-estradiol (E2) treatment on dendritic cells (DCs) in two different mouse models of EAE. The frequency of CD11b(+)/CD11c(+) DCs was significantly decreased in the brain of mice protected from EAE induction by E2 treatment.

Effects of cytokine deficiency on chemokine expression in CNS of mice with EAE.

Although both cytokines and chemokines have been implicated in the pathogenesis of clinical and histological EAE, their interactions in vivo have not yet been clearly established. To address this issue, we evaluated expression of chemokines and receptors in the CNS of wild-type control and cytokine deficient mice at the peak of EAE induced with MOG-35-55 peptide in CFA. Our results demonstrate that: 1) expression of most chemokines/receptors was drastically inhibited in TNF-alpha deficient mice, and was reflective of delayed onset and reduced severity of EAE; 2) distinct patterns of chemokine expression occurred in various other cytokine knockout mice that did not significantly affect expression of clinical EAE; 3) there was a strong association between expression of MIP-1alpha, MIP-2 and MCP-1 in CNS and overall severity of EAE in wild-type and cytokine knockout mice; and 4) among CNS infiltrating cells at the peak of EAE, macrophages and CD8+ T cells were the primary cellular source of most of the chemokines.

Estrogen inhibits systemic T cell expression of TNF-alpha and recruitment of TNF-alpha(+) T cells and macrophages into the CNS of mice developing experimental encephalomyelitis.

Estrogen treatment has been found to have suppressive activity in several models of autoimmunity. To investigate the mechanism of 17 beta-estradiol (E2) suppression of experimental autoimmune encephalomyelitis, we evaluated E2 effects on TNF-alpha expression in the central nervous system (CNS) and spleen of C57BL/6 mice immunized with MOG 35-55/CFA. Kinetic analysis demonstrated that E2 treatment drastically decreased the recruitment of total inflammatory cells as well as TNF-alpha(+) macrophages and T cells into the CNS at disease onset.

Evaluation of the effects of 17beta-estradiol (17beta-e2) on gene expression in experimental autoimmune encephalomyelitis using DNA microarray.

The aim of this study was to identify immune-related genes affected by treatment with 17beta-estradiol (17beta-E2) that contribute to protection of T cell antigen receptor double transgenic mice from experimental autoimmune encephalomyelitis (EAE). The Affymetrix microarray system was used to screen more than 12,000 genes from E2-treated mice protected from EAE vs. control mice with severe EAE.