Cryptococcus neoformans induces IL-8 secretion and CXCL1 expression by human bronchial epithelial cells

<p>Abstract</p> <p>Background</p> <p><it>Cryptococcus neoformans </it>(<it>C. neoformans</it>) is a globally distributed fungal pathogen with the potential to cause serious disease, particularly among immune compromised hosts. Exposure to this organism is believed to occur by inhalation and may result in pneumonia and/or disseminated infection of the brain as well as other organs. Little is known about the role of airway epithelial cells in cryptococcal recognition or their ability to induce an inflammatory response.</p> <p>Methods</p> <p>Immortalized BEAS-2B bronchial epithelial cells and primary normal human bronchial epithelium (NHBE) were stimulated <it>in vitro </it>with encapsulated or acapsular <it>C. neoformans </it>cultivated at room temperature or 37°C. Activation of bronchial epithelial cells was characterized by analysis of inflammatory cytokine and chemokine expression, transcription factor activation, fungal-host cell association, and host cell damage.</p> <p>Results</p> <p>Viable <it>C. neoformans </it>is a strong activator of BEAS-2B cells, resulting in the production of the neutrophil chemokine Interleukin (IL)-8 in a time- and dose-dependent manner. IL-8 production was observed only in response to acapsular <it>C. neoformans </it>that was grown at 37°C. <it>C. neoformans </it>was also able to induce the expression of the chemokine CXCL1 and the transcription factor CAAT/enhancer-binding protein beta (CEBP/β) in BEAS-2B cells. NHBE was highly responsive to stimulation with <it>C. neoformans</it>; in addition to transcriptional up regulation of CXCL1, these primary cells exhibited the greatest IL-8 secretion and cell damage in response to stimulation with an acapsular strain of <it>C. neoformans</it>.</p> <p>Conclusion</p> <p>This study demonstrates that human bronchial epithelial cells mediate an acute inflammatory response to <it>C. neoformans </it>and are susceptible to damage by this fungal pathogen. The presence of capsular polysaccharide and <it>in vitro </it>fungal culture conditions modulate the host inflammatory response to <it>C. neoformans</it>. Human bronchial epithelial cells are likely to contribute to the initial stages of pulmonary host defense <it>in vivo</it>.</p

The Cebpd (C/EBPδ) Gene Is Induced by Luteinizing Hormones in Ovarian Theca and Interstitial Cells But Is Not Essential for Mouse Ovary Function

The CCAAT/enhancer binding protein (CEBP) family of transcription factors includes five genes. In the ovary, both Cebpa and Cebpb are essential for granulosa cell function. In this study we have explored the role of the Cebpd gene in ovarian physiology by expression and functional studies. Here we report that Cebpd (C/EBPδ) is expressed in the mouse ovary in a highly restricted temporal and spatial pattern. In response to luteinizing hormone (LH/hCG), CEBPD expression is transiently induced in interstitial cells and in theca cells of follicles from the primary to pre-ovulatory stage, and overlaps in part with expression of the alpha-smooth muscle actin protein. Efficient down-regulation of CEBPD was dependent on a functional Cebpb gene. Proliferating human theca cells in culture also express Cebpd. Cells from patients with polycystic ovarian syndrome (PCOS) exhibited higher Cebpd expression levels. However, deletion of Cebpd in mice had no overt effect on ovarian physiology and reproductive function. Very little is known at present about the molecular mechanisms underlying theca/interstitial cell functions. The expression pattern of CEBPD reported here identifies a novel functional unit of mouse theca cells of primary through tertiary follicles responding to LH/hCG together with a subset of interstitial cells. This acute stimulation of CEBPD expression may be exploited to further characterize the hormonal regulation and function of theca and interstitial cells

Genetic variation in Fcγ receptor IIa and risk of coronary heart disease: negative results from two large independent populations

Background The role of the Fcgamma receptor IIa (FcgammaRIIa), a receptor for C-reactive protein (CRP), the classical acute phase protein, in atherosclerosis is not yet clear. We sought to investigate the association of FcgammaRIIa genotype with risk of coronary heart disease (CHD) in two large population-based samples. Methods FcgammaRIIa-R/H131 polymorphisms were determined in a population of 527 patients with a history of myocardial infarction and 527 age and gender matched controls drawn from a population-based MONICA- Augsburg survey. In the LURIC population, 2227 patients with angiographically proven CHD, defined as having at least one stenosis [greater than or equal to]50%, were compared with 1032 individuals with stenosis H genotype was not independently associated with lower risk of CHD after multivariable adjustments, neither in the MONICA population (odds ratio (OR) 1.08; 95% confidence interval (CI) 0.81 to 1.44), nor in LURIC (OR 0.96; 95% CI 0.81 to 1.14). Conclusion Our results do not confirm an independent relationship between FcgammaRIIa genotypes and risk of CHD in these populations

CXCL12-Mediated Guidance of Migrating Embryonic Stem Cell-Derived Neural Progenitors Transplanted into the Hippocampus

Stem cell therapies for neurodegenerative disorders require accurate delivery of the transplanted cells to the sites of damage. Numerous studies have established that fluid injections to the hippocampus can induce lesions in the dentate gyrus (DG) that lead to cell death within the upper blade. Using a mouse model of temporal lobe epilepsy, we previously observed that embryonic stem cell-derived neural progenitors (ESNPs) survive and differentiate within the granule cell layer after stereotaxic delivery to the DG, replacing the endogenous cells of the upper blade. To investigate the mechanisms for ESNP migration and repair in the DG, we examined the role of the chemokine CXCL12 in mice subjected to kainic acid-induced seizures. We now show that ESNPs transplanted into the DG show extensive migration through the upper blade, along the septotemporal axis of the hippocampus. Seizures upregulate CXCL12 and infusion of the CXCR4 antagonist AMD3100 by osmotic minipump attenuated ESNP migration. We also demonstrate that seizures promote the differentiation of transplanted ESNPs toward neuronal rather than astrocyte fates. These findings suggest that ESNPs transplanted into the adult rodent hippocampus migrate in response to cytokine-mediated signals

Regional variation in Ascaris lumbricoides and Trichuris trichiura infections by age cohort and sex: effects of market integration among the indigenous Shuar of Amazonian Ecuador

Background: Soil-transmitted helminth (STH) infection peaks during childhood and varies by sex. The impact of market integration (MI) (increasing production for and consumption from a market-based economy) on these infection patterns, however, is unclear. In this study, STH infection is examined by sex and age among indigenous Shuar inhabiting two regions of Amazonian Ecuador: (1) the modestly market-integrated Upano Valley (UV) and (2) the more traditional Cross-Cutucú (CC) region. Methods: Kato-Katz fecal smears were examined for parasite presence and infection intensity. Factorial ANOVAs and post hoc simple effects analyses were performed by sex to compare infection intensity between regions and age categories (infant/child, juvenile/adolescent, adult). Results: Significant age and regional differences in Ascaris lumbricoides and Trichuris trichiura infection were detected. Overall, infants/children and juveniles/adolescents displayed higher parasite loads than adults. CC females exhibited higher A. lumbricoides loads than UV females, while the opposite pattern was observed for T. trichiura infection in males. Conclusions: Regional infection patterns varied by sex and parasite species, perhaps due to MI-linked environmental and lifestyle changes. These results have public health implications for the identification of individuals at risk for infection and contribute to ongoing efforts to track changes and alleviate STH infection in indigenous populations undergoing MI

Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty

Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty

Dysregulation of the C/EBPα Differentiation Pathway in Human Cancer

While much is known about aberrant pathways affecting cell growth and apoptosis, our understanding of another critical step of neoplastic transformation, differentiation arrest, remains poor. The differentiation-inducing transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is required for proper control of adipogenesis, glucose metabolism, granulocytic differentiation, and lung development. Studies investigating the function of this protein in hematopoietic malignancies as well as in lung and skin cancer have revealed numerous ways how tumor cells abrogate C/EBPα function. Genetic and global expression analysis of acute myeloid leukemia (AML) cases identifies C/EBPα-deficient AML as a separate entity yielding novel classification schemes. In patients with a dysfunctional C/EBPα pathway, targeted therapies may overcome the block in differentiation, and in combination with conventional chemotherapy, may lead to complete eradication of the malignant clone. Overall, a better understanding of the mechanisms of how C/EBPα dysregulation participates in the neoplastic process has opened new gateways for differentiation biology research