Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development

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Role of c-kit receptor tyrosine kinase in the development, survival and neoplastic transformation of mast cells

The c-kit gene is allelic with the dominant spotting ( W ) locus on mouse chromosome 5 and encodes a receptor tyrosine kinase. The llgand for c-klt receptor is stem cell factor (SCF), which is the principal growth factor for mast cells. The loss-of-function mutations of c-kit receptor affect the development of mast cells, thereby resulting in a depletion of mast cells. The abundant expression of c-ktt receptor is indispensable for the survival of mast cells. In addition, the galn-of-function mutations of c-kit receptor were found in several tumor mast cell lines. When these galn-of-function mutations were introduced to cells of murine interleukin (IL)-3-dependent cell lines, the expression of c-kit receptor with constitutive tyrosine kinase activity not only abrogated the IL-3 requirement of the cells, but also caused them to become tumorlgenic in nude athymic mice. The gain-of-function mutations of c-kit receptor appear to result in the malignant transformation of mast cells. Taken together, the signals from the c-ktt receptor are essential for the development, survival, and malignant transformation of mast cells.     

Transferrin receptor distribution and iron deposition in the hepatic fobufe of iron-overloaded rats

Under the condition of obvious iron-overload, there is a zonal hernoeiderin (iron) deposition in hepatic lobules. The deposition is heavtest in the periporfal (zone 1) and lightest in the perivenws (zone 3) hepatocytes. However, the mechanism for this pattern of iron deposition is obscure. Hepatic tissues from control, iron-deficlent or ironoverloaded Wistar rats me used to study its pathogenesis. iron-deficiency was Induced by a low Iron regimen. Ironoverload was produced by repeated intraperitoneal injections of ferric nitrilotriace-We (Fe³⁺-NTA) for 1–4 months. Liver tissues of the rats were lmmunohistochemically and histochemically stained for tmnaferrin receptor (TfR), transferrin (Tf), ferritin (Ft), and iron. The staining intensity of TfR, Tf and Ft increased in hepatocytes of iron-deflctent rats and decreased in that of the iromverloaded in comparison with the control rats. TfR atalning was strong in zone 1, with gradual transition into weak staining in zone 3 hepatocytes of the rat liver. TfR located primarily on the hepatocyte membrane. Tf had both membranous and cytoplasmic distribution. Many hepatocytes in group B had strong cytoplasmic Tf staining. Conversely, only a few hepatocytes had weakly stained cytoplasmic Tf in group C. Hepatocytes and Kupffer cells were Ft positive in control rats. Ft was distributed only in the cytoplasm. The staining intensity of Ft was stronger in zone 3 than in zone 1 hepatocytes of iron-deficient rats. In iron-overloaded rats, the iron deposition was severe in zone 1 and mild in zone 3 hepatocytes. These findings suggest that uptake of iron into hepatocytes in vivo is regulated and mediated by TfR and Tf. Gradient TfR distribution from zone 1 to 3 hepatocytes and active TfR-Tf mediated iron uptake resuited in the zonal iron deposition in the hepatic lobule of iron-overloaded rats.     

C1q受体研究进展

补体分子C1q具有调节各种细胞反应的能力.近年,随着C1q功能研究的深入,发现许多细胞内或者细胞表面存在结合C1q的蛋白或者受体,如C1qRp、gC1qbp、C1qRo2-、钙网素/CRT/cC1qR胶凝素受体、CR1.其中某些蛋白除结合C1q外还结合其它配体.     

抗人DR5抗体mDRA- 6细胞毒作用机制分析

目的:探讨鼠抗人DR5单克隆抗体(mAb)mDRA-6对Jurkat细胞的细胞毒作用及其机制。方法:以流式细胞术测定mAbmDRA-6对Jurkat细胞的细胞毒作用和细胞凋亡作用,以及caspase8、9的抑制剂对mAbmDRA-6诱导的Jurkat细胞凋亡的影响。在荧光显微镜下,观察mAbmDRA-6对Jurkat细胞形态的影响。以琼脂糖凝胶电泳检测Jurkat细胞中的DNA片段化。结果:mAbmDRA-6对Jurkat细胞具有显著的细胞毒作用,并呈剂量和时间依赖性。经mAbmDRA-6处理后,Jurkat细胞可出现典型的细胞凋亡的形态特征:细胞膜皱缩,出泡,染色质浓缩,形成凋亡小体等。经mAbmDRA-6处理后,Jurkat细胞膜表面高表达丝氨酸磷脂,并可导致Jurkat细胞中的DNA片段化。caspase8的抑制剂可明显抑制mAbmDRA-6诱导的Jurkat细胞凋亡,caspase9的抑制剂的影响很小。结论:mAbmDRA-6可通过死亡受体信号传导途径诱导Jurakt细胞凋亡,对Jurkat细胞产生细胞毒作用,其在以TRAIL/DR5系统进行的肿瘤治疗和探讨DR5功能结构域方面具有广阔的应用前景。     

mTOR signaling contributes to chondrocyte differentiation.

The mammalian Target Of Rapamycin (mTOR) is a nutrient-sensing protein kinase that regulates numerous cellular processes. Fetal rat metatarsal explants were used as a physiological model to study the effect of mTOR inhibition on chondrogenesis. Insulin significantly enhanced their growth. Rapamycin significantly diminished this response to insulin through a selective effect on the hypertrophic zone. Cell proliferation (bromodeoxyuridine incorporation) was unaffected by rapamycin. Similar observations were made when rapamycin was injected to embryonic day (E) 19 fetal rats in situ. In the ATDC5 chondrogenic cell line, rapamycin inhibited proteoglycan accumulation and collagen X expression. Rapamycin decreased content of Indian Hedgehog (Ihh), a regulator of chondrocyte differentiation. Addition of Ihh to culture medium reversed the effect of rapamycin. We conclude that modulation of mTOR signaling contributes to chondrocyte differentiation, perhaps through its ability to regulate Ihh. Our findings support the hypothesis that nutrients, acting through mTOR, directly influence chondrocyte differentiation and long bone growth.     

Fcγ receptor-mediated phagocytosis requires tyrosine kinase activity and is ligand independent

Receptors for the invariant chain of immunoglobulins (FcR) define the cellular response to specific antigens. FcγR recognize IgG and so elicit a variety of effector functions including phagocytosis. We are interested in the structural determinants for FcγR-mediated phagocytosis, specifically FcγRI(p135) and FcγRIIa isoforms. The low-affinity receptor, FcγRIIa, is found on macrophages and its cytoplasmic domain contains a tyrosine activation motif which has previously been shown to regulate endocytosis. In contrast, FcγRI has no known signaling motifs, though a functional interaction has recently been demonstrated with the γ chain of the high-affinity receptor for IgE, FcεRI. This accessory molecule has a cytoplasmic tyrosine activation motif implicated in signal transduction. Here we demonstrate that although FcγRI transiently expressed on COS-7 cells is able to rosette opsonized SRBC, it cannot phagocytose them. If the cytoplasmic domain of either γ chain or FcγRIIa replaces that of FcγRI in a chimeric receptor, efficient phagocytosis occurs. This particle ingestion is sensitive to the tyrosine kinase inhibitor genistein. Chimeric receptors where the extracellular domain of either FcγRI or FcγRIIa is replaced with that of CD2, a T cell antigen, indicate that FcγR-mediated phagocytosis is ligand independent. We conclude that phagocytosis is dependent upon close particle apposition, tyrosine kinase activity, and that the process is ligand independent.