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During severe sepsis, microvesicles that are positive for tissue factor (TF) are at increased levels within blood and in pulmonary lavage. These microvesicles potentially disperse TF, the major initiator of the coagulation cascade, throughout multiple organ systems, initiating fibrin deposition and resultant ischemia. The source of these microvesicles has remained incompletely defined. Although TF(+) microvesicles are shed from cells that express nascent TF transcript in response to injury, recent findings revealed that circulating, full-length TF protein is detectable prior to these nascent transcripts. This finding suggested that the protein is released from constitutive sources as an acute response. We examined whether Staphylococcus aureus, the Gram-positive bacteria that is emerging as one of the most common etiologic agents in sepsis, is capable of stimulating the release of TF(+) microvesicles from a pulmonary cell line that constitutively expresses TF protein. We found that host cell invasion stimulated an acute release of TF(+) microvesicles and that these microvesicles mediated the transfer of the protein to TF-negative endothelial cells. We also found that transfer was inhibited by cholesterol-lowering simvastatin. Taken together, our findings reveal that S. aureus pathogenesis extends to the acute release of TF(+) microvesicles and that inhibiting dispersal by this mechanism may provide a therapeutic target., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Stat6 is a transcription factor that regulates important cellular processes such as proliferation, differentiation, and survival through mediating IL-4 and IL-13 signaling. Importantly, increasing evidence indicates of a role for Stat6 in lymphoproliferative disorders. Mice expressing a constitutively active form of Stat6 (Stat6VT) primarily in T lymphocytes were generated, and it has been recently described that a small percentage (approximately 5%) of these mice develop a spontaneous lymphoproliferative disorder (LPD) resulting in dramatic splenomegaly and altered splenic cell populations. Here, we report that Stat6VT mice housed in a non-pathogen-free environment have an increased incidence (37%) of the LPD. Additionally, examination of the expression of Stat6-regulated genes known to have roles in tumorigenesis demonstrated that there appears to be no one genetic alteration common to lymphocytes from Stat6VT/LPD mice. Interestingly, however, uniform exposure to antigen via immunization resulted in complete abrogation of the LPD in Stat6VT mice., (Copyright 2009 Elsevier GmbH. All rights reserved.)

Beta1-containing adhesions at the plasma membrane function as dynamic complexes to provide bidirectional communication between the cell and its environment, yet commonly are used by pathogens to gain host cell entry. Recently, the cholesterol-lowering drug simvastatin was found to inhibit host invasion through beta1-containing adhesion complexes. To better understand the regulatory mechanisms controlling adhesion formation and uptake and the use of these complexes by Staphylococcus aureus, the primary etiologic agent in sepsis, bacteremia and endocarditis, we investigated the mechanism of inhibition by simvastatin. In response to simvastatin, adhesion complexes diminished as well as beta1 trafficking to the plasma membrane required to initiate adhesion formation. Simvastatin stimulated CDC42 activation and coupling to p85, a small-guanosine triphosphatase (GTPase) activating protein (GAP), yet sequestered CDC42 coupled to p85 within the cytosol. Loss of p85 GAP activity through use of genetic strategies decreased host cell invasion as well as beta1 trafficking. From these findings, we propose a mechanism whereby p85 GAP activity localized within membrane compartments facilitates beta1 trafficking. By sequestering p85 within the cytosol, simvastatin restricts the availability and uptake of the receptor used by pathogenic strains to gain host cell entry., (Copyright 2009 Elsevier Inc. All rights reserved.)

Signal transducer and activator of transcription 6 (STAT6) is critical for IL-4 and IL-13 responses, and necessary for the normal development of Th2 cells. We previously generated mice that express a constitutively active STAT6 (STAT6VT) under control of the CD2 locus control region, which directs expression to the T-cell compartment. We now describe that a small proportion of these mice (~5%) develop a spontaneous lymphoproliferative disease (LPD) that results in dramatic splenomegaly. The cell populations observed in the LPD spleens can be divided into 2 categories, those that are composed of mixed lineage cells and those that are predominantly T cells with a phenotype similar to that in autoimmune lymphoproliferative syndrome (ALPS) patients. These data suggest that while active STAT6 is not a transforming factor, expression in T cells predisposes toward the development of lymphoproliferative disorders.