Regulated expression of matrix metalloproteinases, inflammatory mediators, and endometrial matrix remodeling by 17beta-estradiol in the immature rat uterus

<p>Abstract</p> <p>Background</p> <p>Administration of a single physiological dose of 17beta-estradiol (E2:40 microg/kg) to the ovariectomized immature rat rapidly induces uterine growth and remodeling. The response is characterized by changes in endometrial stromal architecture during an inflammatory-like response that likely involves activated matrix-metalloproteinases (MMPs). While estrogen is known as an inducer of endometrial growth, its role in specific expression of MMP family members in vivo is poorly characterized. E2-induced changes in MMP-2, -3, -7, and -9 mRNA and protein expression were analyzed to survey regulation along an extended time course 0-72 hours post-treatment. Because E2 effects inflammatory-like changes that may alter MMP expression, we assessed changes in tissue levels of TNF-alpha and MCP-1, and we utilized dexamethasone (600 microg/kg) to better understand the role of inflammation on matrix remodeling.</p> <p>Methods</p> <p>Ovariectomized 21 day-old female Sprague-Dawley rats were administered E2 and uterine tissues were extracted and prepared for transmission electron microscopy (TEM), mRNA extraction and real-time RT-PCR, protein extraction and Western blot, or gelatin zymography. In inhibitor studies, pretreatment compounds were administered prior to E2 and tissues were harvested at 4 hours post-hormone challenge.</p> <p>Results</p> <p>Using a novel TEM method to quantitatively assess changes in stromal collagen density, we show that E2-induced matrix remodeling is rapid in onset (< 1 hour) and leads to a 70% reduction in collagen density by 4 hours. Matrix remodeling is MMP-dependent, as pretreatment with batimastat ablates the hormone effect. MMP-3, -7, and -9 and inflammatory markers (TNF-alpha and MCP-1) are transiently upregulated with peak expression at 4 hours post-E2 treatment. MMP-2 expression is increased by E2 but highest expression and activity occur later in the response (48 hours). Dexamethasone inhibits E2-modulated changes in collagen density and expression of MMPs although these effects are variable. Dexamethasone upregulates MMP-3 mRNA but not protein levels, inhibiting E2-induced upregulation of MMP-7, and -9, and MCP-1 mRNA and protein but not inhibiting the hormone-induced increase in TNF-alpha mRNA.</p> <p>Conclusion</p> <p>The data demonstrate that E2-regulated endometrial remodeling is rapid in onset (<1 hour) and peak expression of MMPs and inflammatory mediators correlates temporally with the period of lowest stromal collagen density during uterine tissue hypertrophy.</p

Spreads in strongly regular graphs

Dedicated to Hanfried Lenz on the occasion of his 80th birthday Abstract. A spread of a strongly regular graph is a partition of the vertex set into cliques that meet Delsarte&apos;s bound (also called Hoffman&apos;s bound). Such spreads give rise to colorings meeting Hoffman&apos;s lower bound for the chromatic number and to certain imprimitive three-class association schemes. These correspondences l ad to conditions for existence. Most examples come from spreads and fans in (partial) geometries. We give other examples, including a spread in the McLaughlin graph. For strongly regular graphs related to regular two-graphs, spreads give lower bounds for the number of non-isomorphic strongly regular graphs in the switching class of the regular two-graph

Spreads in strongly regular graphs

A spread of a strongly regular graph is a partition of the vertex set into cliques that meet Delsarte&apos;s bound (also called Hoffman&apos;s bound). Such spreads give rise to colorings meeting Hoffman&apos;s lower bound for the chromatic number and to certain imprimitive three-class association schemes. These correspondences lead to conditions for existence. Most examples come from spreads and fans in (partial) geometries. We give other examples, including a spread in the McLaughlin graph. For strongly regular graphs related to regular two-graphs, spreads give lower bounds for the number of non-isomorphic strongly regular graphs in the switching class of the regular two-graph

Thinking out of the box - New approaches to controlling GVHD

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD prophylaxis regimens continue to bebased on the combination of a calcineurin inhibitor with an antimetabolite, while first line treatmentsstill relies on high-dose corticosteroids. Further, no second line treatment has emerged thus far in acute or chronic GVHD patients who failed on corticosteroids. After briefly reviewing current standards of GVHD prevention and treatment, this article will discuss recent approaches that might change GVHD prophylaxis / treatment in the next decades, with a special focus on recently developed immunoregulatory strategies based on infusion of mesenchymal stromal or regulatory T-cells, or on injection of lowdose interleukin-2

Convergent Transcription of Interferon-stimulated Genes by TNF-α and IFN-α Augments Antiviral Activity against HCV and HEV

IFN-\xce\xb1 has been used for decades to treat chronic hepatitis B and C, and as an off-label treatment for some cases of hepatitis E virus (HEV) infection. TNF-\xce\xb1 is another important cytokine involved in inflammatory disease, which can interact with interferon signaling. Because interferon-stimulated genes (ISGs) are the ultimate antiviral effectors of the interferon signaling, this study aimed to understand the regulation of ISG transcription and the antiviral activity by IFN-\xce\xb1 and TNF-\xce\xb1. In this study, treatment of TNF-\xce\xb1 inhibited replication of HCV by 71 \xc2\xb1 2.4% and HEV by 41 \xc2\xb1 4.9%. Interestingly, TNF-\xce\xb1 induced the expression of a panel of antiviral ISGs (2-11 fold). Blocking the TNF-\xce\xb1 signaling by Humira abrogated ISG induction and its antiviral activity. Chip-seq data analysis and mutagenesis assay further revealed that the NF-\xce\xba B protein complex, a key downstream element of TNF-\xce\xb1 signaling, directly binds to the ISRE motif in the ISG promoters and thereby drives their transcription. This process is independent of interferons and JAK-STAT cascade. Importantly, when combined with IFN-\xce\xb1, TNF-\xce\xb1 works cooperatively on ISG induction, explaining their additive antiviral effects. Thus, our study reveals a novel mechanism of convergent transcription of ISGs by TNF-\xce\xb1 and IFN-\xce\xb1, which augments their antiviral activity against HCV and HEV