Molecular identification of a danger signal that alerts the immune system to dying cells

In infections, microbial components provide signals that alert the immune system to danger and promote the generation of immunity. In the absence of such signals, there is often no immune response or tolerance may develop. This has led to the concept that the immune system responds only to antigens perceived to be associated with a dangerous situation such as infection. Danger signals are thought to act by stimulating dendritic cells to mature so that they can present foreign antigens and stimulate T lymphocytes. Dying mammalian cells have also been found to release danger signals of unknown identity. Here we show that uric acid is a principal endogenous danger signal released from injured cells. Uric acid stimulates dendritic cell maturation and, when co-injected with antigen in vivo, significantly enhances the generation of responses from CD8+ T cells. Eliminating uric acid in vivo inhibits the immune response to antigens associated with injured cells, but not to antigens presented by activated dendritic cells. Our findings provide a molecular link between cell injury and immunity and have important implications for vaccines, autoimmunity and inflammation.     

Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.     

Expression of human growth hormone-releasing factor in transgenic mice results in increased somatic growth

The neurohumoral regulation of growth hormone secretion is mediated in part by two hypothalamic peptides that reach the anterior pituitary via the hypothalamo-hypophysial portal blood system. Somatostatin inhibits the release of growth hormone, whereas growth hormone-releasing factor (GRF) positively regulates both growth hormone synthesis and secretion. Two forms of human GRF, 40 and 44 amino acids long, have been characterized from extra-hypothalamic tumours as well as from the hypothalamus. Analysis of human GRF complementary DNA and genomic clones indicates that the GRF peptides are first synthesized as a 107- or 108-amino-acid precursor protein. To examine the physiological consequences of GRF expression, we have established strains of transgenic mice containing a fusion gene including the promoter/regulatory region of the mouse metallothionein-I (MT-I) gene and the coding region of the human GRF gene. We report that expression of the human GRF precursor protein in these animals results in measurable levels of human GRF and increased levels of mouse growth hormone in plasma and accelerated growth rates relative to control littermates. These results demonstrate a direct role for GRF in the positive regulation of somatic growth. Unexpectedly, female transgenic mice carrying the MT-GRF fusion gene are fertile, in contrast to female transgenic mice expressing human or rat growth hormone, which are generally infertile. These transgenic mouse strains should provide useful animal models for the study of several types of human growth disorders.     

Stimulation of specific GTP binding and hydrolysis activities in lymphocyte membrane by interleukin-2

Interleukin-2 (IL-2) is a polypeptide growth factor which stimulates the proliferation and differentiation of T lymphocytes. The receptor for IL-2 is expressed on activated T lymphocytes, cloned IL-2 dependent cells and several other cell types. Analysis of the primary structure and of immune-precipitated receptor suggests that this molecule has no intrinsic signal transduction function, unlike other growth factors. IL-2 interaction with a high affinity receptor has been shown, however, to activate the calcium/phospholipid-dependent protein kinase C (PK-C) presumably via phosphoinositide hydrolysis. Members of a family of closely related guanine nucleotide binding proteins (G proteins) regulate a diverse group of metabolic events. Two of them, Gs and Gi, stimulate and inhibit adenylate cyclase activity respectively, and other G proteins are involved in diverse signal transduction system. Another member, Go, has no known function and activation of phospholipase C has been attributed to the action of an unidentified G protein, Gp. Since it has been observed that IL-2 inhibits the catalytic activity of adenylate cyclase and that agents such as PGE2 which stimulate adenylate cyclase activity inhibit the lymphoproliferative response to IL-2, association of GTP binding proteins with IL-2 signal transduction was investigated. In this report we describe for the first time the participation of a GTP binding protein in the action of a polypeptide growth factor, interleukin-2.     

γ-Al2O3载体孔内原位合成水滑石

以尿素为沉淀剂,利用γ-Al2O3的内孔表面铝源原位合成水滑石. 考察了晶化时间、晶化温度、初始溶液浓度、原料配比对原位合成水滑石的影响. 实验中发现晶化6 h,MgAlCO3-LDH的晶体结构已趋于完整,晶化时间大于6 h时会有NH4Al(OH)2CO3*H2O杂相生成.在实验条件范围内,生成的一次粒子大小随着晶化时间的延长逐渐增大,随着晶化温度的升高、初始溶液浓度的增大而减小.     

Hormonal manipulation of carrageenin-induced pyresis in rats

Summary The intensity of the hyperthermic response in rats promoted by subplantar injection of 1 mg of carrageenin is directly related to the irritant properties of the type of carrageenin. The overall pyretic response is more dramatic in female rats than in male rats. Subtle changes in the time-course hyperthermic profiles are seen after hormonal modifications.This work was supported by NIH, MBS research grant No. RR08111.     

Domain structure of human glucocorticoid receptor and its relationship to the v-erb-A oncogene product

The interaction of steroids with their nuclear receptors induces a cascade of regulatory events that results from the activation of specific sets of genes by the hormone/receptor complex. Steroids, either acting alone or possibly synergistically with other growth factors, can influence the DNA synthesis and proliferation of specific target cells, initiate developmental pathways and activate expression of the differentiated phenotype. Moreover, steroid hormones have been implicated in abnormal growth regulation both in tumours and tumour-derived cell lines. The identification of complementary DNAs encoding the human glucocorticoid receptor (hGR) predicts two protein forms (alpha and beta; 777 and 742 amino acids long, respectively) which differ at their carboxy termini. We report here that both forms of the receptor are related, with respect to their domain structure, to the v-erb-A oncogene product of avian erythroblastosis virus (AEV), which suggests that steroid receptor genes and the c-erb-A proto-oncogene are derived from a common primordial regulatory gene. Therefore, oncogenicity by AEV may result, in part, from the inappropriate activity of a truncated steroid receptor or a related regulatory molecule encoded by v-erb-A. This suggests a mechanism by which transacting factors may facilitate transformation. We also identify a short region of hGR that is homologous with the Drosophila homoeotic proteins encoded by Antennapedia and fushi tarazu.