The tumor necrosis factor (TNF) superfamily of cytokines includes both soluble and membrane-bound proteins that regulate immune responses. A member of the human TNF family, BLyS (B lymphocyte stimulator), was identified that induced B cell proliferation and immunoglobulin secretion. BLyS expression on human monocytes could be up-regulated by interferon-gamma. Soluble BLyS functioned as a potent B cell growth factor in costimulation assays. Administration of soluble recombinant BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum immunoglobulin concentrations. The B cell tropism of BLyS is consistent with its receptor expression on B-lineage cells. The biological profile of BLyS suggests it is involved in monocyte-driven B cell activation.

Bacterial pathogenicity islands (PAI) often encode both effector molecules responsible for disease and secretion systems that deliver these effectors to host cells. Human enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli, and the mouse pathogen Citrobacter rodentium (CR) possess the locus of enterocyte effacement (LEE) PAI. We systematically mutagenized all 41 CR LEE genes and functionally characterized these mutants in vitro and in a murine infection model. We identified 33 virulence factors, including two virulence regulators and a hierarchical switch for type III secretion. In addition, 7 potential type III effectors encoded outside the LEE were identified by using a proteomics approach. These non-LEE effectors are encoded by three uncharacterized PAIs in EHEC O157, suggesting that these PAIs act cooperatively with the LEE in pathogenesis. Our findings provide significant insights into bacterial virulence mechanisms and disease. D iarrheagenic enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), and Citrobacter rodentium (CR) are attaching͞effacing (A͞E) bacterial pathogens that attach to host intestinal epithelium and efface brush border microvilli, forming A͞E lesions (1, 2). EHEC and EPEC represent a significant threat to human health. Sequencing the genome of EHEC O157:H7, the causative agent of ''Hamburger disease'' and the most common serotype associated with food and water poisoning, has identified many putative virulence factors (3). These factors are often encoded by pathogenicity islands (PAI) present in the genomes of pathogenic, but not closely related nonpathogenic, strains (4). However, the functions of the PAIs in virulence have not been systematically analyzed.Many key virulence factors shared by A͞E pathogens reside in the locus of enterocyte effacement (LEE), a PAI essential for A͞E lesion formation (5-8). The LEE contains 41 genes and encodes a type III secretion system (TTSS), a common virulence mechanism for many human and plant pathogens (4, 9, 10). TTSSs are conserved organelles that deliver bacterial effector proteins capable of modulating host functions into host cells. The LEE encodes proteins for forming such an organelle (2), but the LEE genes involved in assembling and regulating this apparatus have not been defined.The LEE also encodes a regulator (Ler), an adhesin (intimin) and its receptor (Tir) responsible for intimate attachment, several secreted proteins, and their chaperones (1, 2). The secreted proteins consist of effectors as well as translocators (EspA, EspD, and EspB) required for translocating effectors into host cells. Five LEEencoded effectors (Tir, EspG, EspF, Map, and EspH) have been identified, which are involved in modulating host cytoskeleton (2, 11). However, nearly half of the LEE genes have no homologs and have not been functionally studied.Because EHEC and EPEC are human pathogens, efforts aimed at elucidating the function of the LEE have primarily been restricted to in vitro studies. Animal models, including neonatal...

Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.