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Receptor Type II (receptor + type_ii)
Selected AbstractsEffects of insulin resistance on endothelial function: possible mechanisms and clinical implicationsDIABETES OBESITY & METABOLISM, Issue 10 2008D Tousoulis Insulin resistance (IR) is defined as a reduced responsiveness of peripheral tissues to the effects of the hormone, referring to abated ability of insulin in stimulating glucose uptake in peripheral tissues and in inhibiting hepatic glucose output. Insulin has both a vasodilatory effect, which is largely endothelium dependent through the release of nitric oxide, and a vasoconstrictory effect through the stimulation of the sympathetic nervous system and the release of endothelin-1. IR and endothelial dysfunction (ED) are not only linked by common pathogenetic mechanisms, involving deranged insulin signalling pathways, but also by other, indirect to the hormone's actions, mechanisms. Different treatment modalities have been proposed to affect positively both the metabolic effects of insulin and ED. Weight loss has been shown to improve sensitivity to insulin as a result of either altered diet or exercise. Exercise has favourable effects on endothelial function in normal states and in states of disease, in men and women, and throughout the age spectrum and, hence, in IR states. Metformin improves sensitivity to insulin and most likely affects positively ED. Studies have shown that inhibitors of the renin,angiotensin system alter IR favourably, while Angiotensin converting enzyme (ACE) inhibitors and Angiotensin receptor type II (ATII) inhibitors improve ED. Ongoing studies are expected to shed more light on the issue of whether treatment with the thiazolidinediones results in improvement of endothelial function, along with the accepted function of improving insulin sensitivity. Finally, improved endothelial function by such treatments is not in itself proof of reduced risk for atherosclerosis; this remains to be directly tested in clinical trials. [source] Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor , resistant cellsGENES, CHROMOSOMES AND CANCER, Issue 2 2008Swati Biswas The mutational inactivation of transforming growth factor , receptor type II (TGFBR2) occurs in ,30% of colon cancers and promotes the formation of colon cancer by inhibiting the tumor suppressor activity of the TGFB signaling pathway. TGFBR2 mutations occur in >90% of microsatellite unstable (MSI) colon cancers and affect a polyadenine tract in exon 3 of TGFBR2, called BAT-RII, which is vulnerable to mutation in the setting of DNA mismatch repair (MMR) system deficiency. In light of the vulnerable nature of the BAT-RII tract in the setting of MMR inactivation and the favorable effects of TGFBR2 inactivation in colon cancer, analysis of TGFBR2 inactivation provides an opportunity to assess the roles of genomic instability vs. clonal selection in cells acquiring TGFBR2 BAT-RII tract mutations in MSI colon cancer formation. The contribution of genomic instability and/or clonal evolution to the mutational inactivation of TGBFR2 in MSI colon cancers has not been studied in a systematic way that would allow a determination of the relative contribution of these two mechanisms in the formation of MSI colon cancer. It has not been demonstrated whether the BAT-RII tract mutations are strictly a consequence of the BAT-RII region being hypermutable in the setting of MMR deficiency or if the mutations are rather a consequence of clonal selection pressure against the TGFB receptor. Through the use of defined cell line systems, we show that both genomic instability and clonal selection of TGFB resistant cells contribute to the high frequency of TGFBR2 mutations in MSI colon cancer. © 2007 Wiley-Liss, Inc. [source] The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factor ,1-specific receptors on promonocytic U937 cell membranesAGING CELL, Issue 2 2009Simona Gargiulo Summary Among the broad variety of compounds generated via oxidative reactions in low-density lipoproteins (LDL) and subsequently found in the atherosclerotic plaque are aldehydes that are still esterified to the parent lipid, termed core aldehydes. The most represented cholesterol core aldehyde in LDL is 9-oxononanoyl cholesterol (9-ONC), an oxidation product of cholesteryl linoleate. 9-ONC, at a concentration detectable in biological material, markedly up-regulates mRNA expression and protein level of both the pro-fibrogenic and pro-apoptotic cytokine transforming growth factor ,1 (TGF-,1) and the TGF-, receptor type I (T,RI) in human U937 promonocytic cells. We also observed increased membrane presentation of TGF-, receptor type II (T,RII). Experiments employing the T,RI inhibitor SB431542, or the TGF, antagonist DANFc chimera, have shown that the effect on T,RI is directly induced by 9-ONC, while T,RII up-regulation seems stimulated by its specific ligand, i.e. TGF,1, over-secreted meanwhile by treated cells. Increased levels of the cytokine and of its specific receptors in 9-ONC-treated cells clearly occurs through stimulation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), as demonstrated by ERK1/2 knockdown experiments using mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MEK1 and MEK2) siRNAs, or PD98059, a selective MEK1/2 inhibitor. 9-ONC might thus sustain further vascular remodeling due to atherosclerosis, not simply by stimulating synthesis of the pro-fibrogenic cytokine TGF-,1 in vascular cells, but also and chiefly by enhancing the TGF-,1 autocrine loop, because of the marked up-regulation of the cytokine's specific receptors T,RI and T,RII. [source] NF,B Activation in Mouse Pituitary: Comparison of Response to Interleukin-1, and LipopolysaccharideJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2003P. Parnet Abstract The mouse anterior pituitary contains both types of interleukin (IL)-1 receptors, IL-1 receptor type I (IL-1RI) and IL-1 receptor type II (IL-1RII). These receptors are expressed mainly on somatotroph cells. In the present study, the ability of the mouse pituitary to respond in vivo to IL-1 or to lipopolysaccharide (LPS) was demonstrated by measuring, with an electrophoretic mobility shift assay, the presence of an active NF,B complex in cell nuclei from pituitaries of mice injected intraperitoneally with recombinant rat-IL-1, or LPS. Using immunohistochemistry with an antibody directed against the p65 NF,B subunit, a rapid and transient NF,B response to LPS was observed. This response was present predominantly in the nuclei of glial fibrillary acidic protein (GFAP)-positive cells and F4/80-labelled cells of the posterior and the anterior pituitary 15 min after stimulation and became faint after 2 h. In comparison, the early and strong NF,B response to IL-1, treatment was localized into somatotroph cells, GFAP positive cells and F4/80-labelled cells of the posterior and anterior pituitary. Activation of NF,B in response to IL-1, was no longer apparent in IL-1RI knockout mice, confirming that this receptor is essential for the transduction of IL-1 signal in the pituitary, but remained after LPS treatment. In addition, we investigated the effect of IL-1 on target genes by measuring the mRNA and proteins synthesis of growth hormone (GH), IL-6 and IL-1ra in the pituitary and the plasma. IL-1, was shown to induce a rapid and strong synthesis of IL-6 and IL-1ra in the pituitary but failed to regulate GH contents or release. These data suggest that the pituitary is able to respond to a systemic infection via cytokine-mediated responses transduced by IL-1. [source] Correlation Between Decreased Type-II Interleukin-1 Receptor and Increased Monocyte Chemotactic Protein-1 Expression in the Endometrium of Women with EndometriosisAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 4 2001ABDELAZIZ KHARFI PROBLEM: Monocyte chemotactic protein-1 (MCP-1), a potent inducer of macrophage recruitment and activation, is overexpressed in the eutopic endometrium of women with endometriosis. Eutopic endometrial cells of women with endometriosis secrete higher levels of MCP-1 than those of normal women, following stimulation with interleukin-1 (IL-1). The aim of this study was to examine whether there is any correlation between the expression of IL-1 receptor type II (IL-1RII), a specific downregulator of IL-1 activity, and that of MCP-1 in the eutopic endometrium of women with endometriosis. METHOD OF STUDY: Endometrial biopsies of 46 women with endometriosis and 22 healthy women were evaluated simultaneously for IL-1RII and MCP-1 expression by immunohistochemistry. RESULTS: Our study revealed a highly significant correlation between the decreased expression of IL-1RII and the increased expression of MCP-1 in the endometrial tissue of women with endometriosis (Spearman correlation coefficient r=,0.377, P=0.002), particularly in the initial stages of the disease (stages I and II; r=,0.368, P=0.020 and r=,0.480, P=0.002, respectively). Furthermore, this correlation was observed in the proliferative (r=,0.366, P=0.047) and the secretory phases (r=,0.321, P=0.049) of the menstrual cycle. CONCLUSIONS: These results suggest that the reduced capability of endometrial tissue to downregulate IL-1 proinflammatory effects may be involved in the increased expression of MCP-1 in the endometrium of women with endometriosis and the establishment of an inflammatory state. The results also indicate a sustained process of cell activation throughout the menstrual cycle. [source] Genetic engineering to study testicular tumorigenesisAPMIS, Issue 1 2003WEI YAN In humans, Sertoli cell tumors account for approximately 4% of all testicular tumors, and 20% of these are malignant. The mechanisms underlying Sertoli cell tumorigenesis remain largely unknown. Using gene knockout technology, we previously generated mutant mice lacking the , subunit of inhibin dimers. The inhibin ,-null male mice develop testicular Sertoli cell tumors with 100% penetrance. These tumors develop as early as 4 weeks of age and cause a cachexia-like wasting syndrome. Castrated inhibin , knockout mice develop sex steroidogenic adrenal cortical tumors. These studies have identified inhibins as secreted tumor suppressors with specificity for the gonads and adrenal glands. It had been suggested that endocrine factors play roles in Sertoli cell tumorigenesis by altering cell cycle machinery of the Sertoli cells. To test the potential of these factors to function as modifiers of Sertoli cell tumorigenesis, we have employed a genetic intercross strategy, breeding inhibin , mutant mice with mutant mice deficient in endocrine signaling factors including gonadotropin releasing hormone (hypogonadal, hpg mice), follicle stimulating hormone, anti-Müllerian hormone (MH), activin receptor type II, or androgen receptor (testicular feminization, tfm mice), or mice overexpressing follistatin. We are also investigating the effects of loss of critical cell cycle regulators, such as cyclin dependent kinase inhibitor p27, on Sertoli cell tumorigenesis in inhibin , knockout males. These studies clearly demonstrate the roles of these factors as modifiers of the Sertoli cell tumorigenesis. Activin signaling through activin receptor type II is responsible for the cachexia-like syndrome observed in the inhibin , knockout mice with tumors. The gonadotropin hormones are essential for testicular tumor development, but elevated FSH levels are not sufficient to cause Sertoli cell tumors. Absence of FSH, lack of androgen receptor, or overexpression of follistatin slows the tumor growth and minimizes the cachexia symptoms, thus prolonging the life span of these double mutant mice. In contrast, absence of AMH or p27 causes earlier onset and more aggressive development of testicular tumor, with an earlier death of double mutant mice. We are currently investigating roles of estrogen signaling pathways, and other cell cycle regulators, in tumor development in the inhibin , knockout mice by generating mice with double or triple mutations. Genetic engineering in mouse models provides a powerful tool to study the mechanisms of testicular tumorigenesis and define the important genetic modifiers in vivo. [source] Prolactin alters the mechanisms of B cell tolerance inductionARTHRITIS & RHEUMATISM, Issue 6 2009Subhrajit Saha Objective Autoimmune diseases predominantly affect women, suggesting that female sex hormones may play a role in the pathogenesis of such diseases. We have previously shown that persistent mild-to-moderate elevations in serum prolactin levels induce a break in self tolerance in mice with a BALB/c genetic background. The aim of this study was to evaluate the effects of hyperprolactinemia on the mechanisms of B cell tolerance induction. Methods Effects of prolactin on splenic B cell subsets were studied in female BALB/c mice. B cell receptor (BCR),mediated apoptosis and proliferation of transitional B cells were analyzed by flow cytometry. Expression of apoptotic genes was examined by microarrays and real-time polymerase chain reaction analysis. B cells coexpressing ,/, light chains were assessed by flow cytometry and immunohistochemistry. Activation status of transitional type 3 (T3) B cells was evaluated by BCR-induced calcium influx studies. Results BCR-mediated apoptosis of the T1 B cell subset, a major checkpoint for negative selection of autoreactive specificities, was decreased in prolactin-treated mice. Microarray studies indicated that this event may be mediated by the prolactin-induced up-regulation of the antiapoptotic gene interferon-, receptor type II and down-regulation of the proapoptotic gene Trp63. Prolactin treatment also altered the amount of receptor editing, as indicated by the increased number of transitional B cells coexpressing ,/, light chains. Additionally, hyperprolactinemia modified the level of B cell anergy by increasing the degree of BCR-induced calcium influx in the T3 B cells. Conclusion Persistently elevated serum prolactin levels interfere with B cell tolerance induction by impairing BCR-mediated clonal deletion, deregulating receptor editing, and decreasing the threshold for activation of anergic B cells, thereby promoting autoreactivity. [source] Mutations and Reduced Expression of the Transforming Growth Factor-, Receptor II Gene in Rat Lung Adenocarcinomas Induced by N -Nitrosobis-(2-hydroxypropyl)amineCANCER SCIENCE, Issue 11 2000Toshifumi Tsujiuchi Mutations and expression of the transforming growth factor-, receptor type II (TGF-,RII) gene were investigated in lung adenocarcinomas induced by N -nitrosobis(2-hydroxypropyl)amine (BHP) in rats. Males of the Wistar strain, 6 weeks old, were given 2000 ppm of BHP in their drinking water for 12 weeks and then maintained without further treatment until killed at week 25. Total RNA was extracted from 12 adenocarcinomas and mutations in TGF-,RII were investigated by RT-PCR-restriction-SSCP analysis followed by sequencing analysis. Two out of 12 adenocarcinomas showed band shifts, indicative of mutations (16.7%). One was a CTG-to-TTG (Leu to Leu) transition at codon 308 without amino acid alteration and the other a frameshift deletion of one of two guanines at nucleotides 1434 to 1435 (codon 477 to 478). Semi-quantitative RT-PCR analysis demonstrated significantly reduced TGF-,RII expression in adenocarcinomas, as compared with normal lung tissue. These results suggest that TGF-,RII alterations may play a role in the acquisition of growth advantage by lung adenocarcinomas induced by BHP in rats. [source] | |||||||||||||||||||