Fibroblasts are the primary cell type responsible for synthesis and remodeling of the extracellular matrix in the heart. A number of factors including growth factors, hormones and mechanical forces have been identified that modulate the production of extracellular matrix by cardiac fibroblasts. Inflammatory mediators including proinflammatory cytokines and chemokines also impact fibrosis of the heart. Recent studies have illustrated that interleukin-18 promotes a profibrotic response in cardiac fibroblasts; however the effects of this cytokine on other aspects of fibroblast function have not been examined. While fibroblasts have long been known for their role in production and remodeling of the extracellular matrix, other functions of these cells are only now beginning to be appreciated. We hypothesize that exposure to interleukin-18 will stimulate other aspects of fibroblast behavior important in myocardial remodeling including proliferation, migration and collagen reorganization. Fibroblasts were isolated from adult male rat hearts and bioassays performed to determine the effects of interleukin-18 on fibroblast function. Treatment of fibroblasts with interleukin-18 (1-100 ng/ml) resulted in increased production of extracellular matrix components and remodeling or contraction of three-dimensional collagen scaffolds by these cells. Furthermore, exposure to interleukin-18 stimulated fibroblast migration and proliferation. Treatment of heart fibroblasts with interleukin-18 resulted in the rapid activation of the c-Jun N-terminal kinase (JNK) and Phosphoinositide 3-kinase (PI3-kinase) pathways. Studies with pharmacological inhibitors illustrated that activation of these pathways is critical to interleukin-18 mediated alterations in fibroblast function. These studies illustrate that interleukin-18 plays a role in modulation of cardiac fibroblast function and may be an important component of the inflammation-fibrosis cascade during pathological myocardial remodeling.

Although the percentage of parturients achieving adequate labor analgesia at 10 minutes after epidural bolus did not differ by technique, DPE was associated with faster time to VAS ≤ 10 mm compared with LE.

Antigen engagement of the T-cell receptor (TCR) induces a rapid and dramatic decondensation of chromatin that is necessary for T-cell activation. This decondensation makes T-cells competent to respond to Interleukin-2 providing a mechanism to ensure clonotypic proliferation during an immune response. Using murine T-cells, we investigated the mechanism by which TCR signaling can initiate chromatin decondensation, focusing on the role of calcium mobilization. During T-cell activation, calcium is first released from intracellular stores, followed by influx of extracellular calcium via store operated calcium entry. We show that mobilization of intracellular calcium is required for TCR-induced chromatin decondensation. However, the decondensation is not dependent on the activity of the downstream transcription factor NFAT. Furthermore, we show that the influx of extracellular calcium is dispensable for initiating chromatin decondensation. Finally, we show that mobilization of calcium from intracellular stores is sufficient to induce decondensation, independent of TCR engagement. Collectively, our data suggest that chromatin decondensation in peripheral T-cells is controlled by modulating intracellular calcium levels.

No abstract

Condensation of chromatin within the nucleus of T lymphocytes occurs during thymocyte development and is a requirement for proper T cell development and maintenance of the naïve (quiescent) state. T cell activation via stimulation of the T cell receptor (TCR) is a necessary step in an immune response, allowing T cells to gain the ability to proliferate in response to cytokines, such as IL-2. During this activation process, the chromatin within T cells decondenses, allowing access to the previously inaccessible DNA, permitting the transcription of genes required for proliferation. We demonstrate that stimulation of either the IP¬3 (inositol triphosphate) or DAG (diacylglycerol) pathways downstream of the TCR leads to chromatin decondensation, but with different kinetics. Within the IP3 pathway, we show that extracellular calcium is not required for the initial decondensation of chromatin. Furthermore, we show that the release of calcium from intracellular stores is sufficient and required for the initial decondensation of chromatin following TCR engagement. Interestingly, while calcium mobilization results in a decondensation of chromatin, it is not sufficient for STAT5 target gene expression. However, chromatin decondensation via the DAG pathway is capable of making T cells competent to respond to IL-2. These findings suggest that there may be at least two distinct domains of condensed chromatin in naïve T cells.