Flagellin Activates NAIP/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages.

Infection of human macrophages with serovar Typhimurium ( Typhimurium) leads to inflammasome activation. Inflammasomes are multiprotein complexes facilitating caspase-1 activation and subsequent gasdermin D-mediated cell death and IL-1β and IL-18 cytokine release. The NAIP/NLRC4 inflammasome is activated by multiple bacterial protein ligands, including flagellin from the flagellum and the needle protein PrgI from the Typhimurium type III secretion system.

Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling.

Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (T) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear.

IL-1α cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence-associated secretory phenotype.

Interleukin-1 alpha (IL-1α) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL-1α is produced after inflammasome activation and during cell senescence, but the protease cleaving IL-1α in these contexts is unknown. We show IL-1α is activated by caspase-5 or caspase-11 cleavage at a conserved site.

New concepts in Chlamydia induced inflammasome responses.

Since the concept of the inflammasome was introduced by Martinon, Burns and Tschopp in 2002, there has been an exponential increase in our understanding of how inflammasomes (caspase activating molecular platforms) regulate innate inflammatory responses to infectious microorganisms. Advances in understanding inflammasome biology have been developed using a range of bacterial pathogens. Recent studies investigating inflammasome responses during Chlamydia infection have provided interesting mechanistic insights in to inflammasome activation during intracellular bacterial infection.

β-Glucan Size Controls Dectin-1-Mediated Immune Responses in Human Dendritic Cells by Regulating IL-1β Production.

Dectin-1/CLEC7A is a pattern recognition receptor that recognizes β-1,3 glucans, and its stimulation initiates signaling events characterized by the production of inflammatory cytokines from human dendritic cells (DCs) required for antifungal immunity. β-glucans differ greatly in size, structure, and ability to activate effector immune responses from DC; as such, small particulate β-glucans are thought to be poor activators of innate immunity. We show that β-glucan particle size is a critical factor contributing to the secretion of cytokines from human DC; large β-glucan-stimulated DC generate significantly more IL-1β, IL-6, and IL-23 compared to those stimulated with the smaller β-glucans.

Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection.

The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an organism that causes significant immunopathology, we sought to determine critical host and pathogen factors that contribute to the induction of inflammasome activation. We assayed inflammasome activation by immunoblotting and ELISA to detect IL-1β processing and LDH release to determine pyroptosis.

IRE1α mediates PKR activation in response to Chlamydia trachomatis infection.

Protein kinase RNA activated (PKR) is a crucial mediator of anti-viral responses but is reported to be activated by multiple non-viral stimuli. However, mechanisms underlying PKR activation, particularly in response to bacterial infection, remain poorly understood. We have investigated mechanisms of PKR activation in human primary monocyte-derived dendritic cells in response to infection by Chlamydia trachomatis.

Regulation of GTP-binding protein (Gαs) expression in human myometrial cells: a role for tumor necrosis factor in modulating Gαs promoter acetylation by transcriptional complexes.

The onset of parturition is associated with a number of proinflammatory mediators that are themselves regulated by the nuclear factor κB (NF-κB) family of transcription factors. In this context, we previously reported that the RelA NF-κB subunit represses transcription and mRNA expression of the proquiescent Gαs gene in human myometrial cells following stimulation with the proinflammatory cytokine TNF. In the present study, we initially defined the functional consequence of this on myometrial contractility.

Distinct cell death programs in monocytes regulate innate responses following challenge with common causes of invasive bacterial disease.

Peripheral blood monocytes represent the rapid response component of mononuclear phagocyte host defense, generating vigorous but finite antibacterial responses. We investigated the fate of highly purified primary human monocytes following phagocytosis of different bacteria. Exposure to high bacterial loads resulted in rapid loss of cell viability and decreased functional competence.

Characterisation and expression of SPLUNC2, the human orthologue of rodent parotid secretory protein.

We recently described the Palate Lung Nasal Clone (PLUNC) family of proteins as an extended group of proteins expressed in the upper airways, nose and mouth. Little is known about these proteins, but they are secreted into the airway and nasal lining fluids and saliva where, due to their structural similarity with lipopolysaccharide-binding protein and bactericidal/permeability-increasing protein, they may play a role in the innate immune defence. We now describe the generation and characterisation of novel affinity-purified antibodies to SPLUNC2, and use them to determine the expression of this, the major salivary gland PLUNC.

Expression of Tie-2 by human monocytes and their responses to angiopoietin-2.

Angiopoietins 1 and 2 bind to Tie-2 expressed on endothelial cells and regulate vessel stabilization and angiogenesis. Tie-2(+) monocytes have been shown to be recruited to experimental tumors where they promote tumor angiogenesis. In this study, we show that 20% of CD14(+) human blood monocytes express Tie-2, and that these cells coexpress CD16 (FcgammaRIII) and are predominantly CD34 negative.

Liverpool Telecare Pilot: case studies.

Telecare services use information and communications technology (ICT) to support the provision of care to people in their own homes. This paper describes a pilot telecare service employed by Liverpool (UK) City Council to support a sample of their frail and elderly social services users. The pilot has been running for over two years and has been deployed for 21 individuals in Liverpool.

Radiation cost of helical high-resolution chest CT.

Objective: In our department, most high-resolution CT (HRCT) scans of the lungs are performed in conjunction with a standard helical examination to assess the entire chest. This requires scanning the patient twice. The goal of this study was to determine if the radiation dose could be decreased by performing a single combination helical scan of the chest from which both 5-mm standard and 1.

Distinguishing and combining risks for sexual and violent recidivism.

A two-dimensional risk assessment system for sexual offenders was created that can classify them for risk of sexual recidivism, risk of nonsexual violent recidivism, and the composite risk of reconviction for sexual or nonsexual assaults. Receiver operating characteristic (ROC) analyses of separate follow-up samples were used for cross-validation. The system is easier to score than Static-99, and substantially easier to score than the VRAG or SORAG, while yielding comparable predictive accuracy in cross-validation samples with follow-ups from 2 years to 19 years.

Peritoneal fluid values and collection technique in young, normal calves.

Peritoneal fluid from 10 healthy young male Holstein calves was analyzed three times (2 to 3 days, 12 to 15 days and 27 to 30 days) during the first month of life. A new technique for collection of peritoneal fluid from calves positioned in left lateral recumbency was developed. The technique was found to be reliable and without noticeable complications.