E1A expression dysregulates IL-8 production and suppresses IL-6 production by lung epithelial cells

BACKGROUND: The adenoviral protein E1A has been proposed to play a role in the pathophysiology of COPD, in particular by increasing IL-8 gene transcription of lung epithelial cells in response to cigarette smoke-constituents such as LPS. As IL-8 production is also under tight post-transcriptional control, we planned to study whether E1A affected IL-8 production post-transcriptionally. The production of IL-6 by E1A-positive cells had not been addressed and was studied in parallel. Based on our previous work into the regulation of IL-8 and IL-6 production in airway epithelial cells, we used the lung epithelial-like cell line NCI-H292 to generate stable transfectants expressing either E1A and/or E1B, which is known to frequently co-integrate with E1A. We analyzed IL-8 and IL-6 production and the underlying regulatory processes in response to LPS and TNF-α. METHODS: Stable transfectants were generated and characterized with immunohistochemistry, western blot and flow cytometry. IL-8 and IL-6 protein production was measured by ELISA. Levels of IL-8 and IL-6 mRNA were measured using specific radiolabeled probes. EMSA was used to assess transcriptional activation of relevant transcription factors. Post-transcriptional regulation of mRNA half-life was measured by Actinomycin D chase experiments. RESULTS: Most of the sixteen E1A-expressing transfectants showed suppression of IL-6 production, indicative of biologically active E1A. Significant but no uniform effects on IL-8 production, nor on transcriptional and post-transcriptional regulation of IL-8 production, were observed in the panel of E1A-expressing transfectants. E1B expression exerted similar effects as E1A on IL-8 production. CONCLUSION: Our results indicate that integration of adenoviral DNA and expression of E1A and E1B can either increase or decrease IL-8 production. Furthermore, we conclude that expression of E1A suppresses IL-6 production. These findings question the unique role of E1A protein in the pathophysiology of COPD, but do not exclude a role for adenoviral E1A/E1B DNA in modulating inflammatory responses nor in the pathogenesis of COPD

Self-report and parent-report of physical and psychosocial well-being in Dutch adolescents with type 1 diabetes in relation to glycemic control

BACKGROUND: To determine physical and psychosocial well-being of adolescents with type 1 diabetes by self-report and parent report and to explore associations with glycemic control and other clinical and socio-demographic characteristics. METHODS: Demographic, medical and psychosocial data were gathered from 4 participating outpatient pediatric diabetes clinics in the Netherlands. Ninety-one patients completed the Child Health Questionnaire-CF87 (CHQ-CF87), Centre for Epidemiological Studies scale for Depression (CES-D), and the DFCS (Diabetes-specific Family Conflict Scale). Parents completed the CHQ-PF50, CES-D and the DFCS. RESULTS: Mean age was 14.9 years (± 1.1), mean HbA(1c )8.8% (± 1.7; 6.2–15.0%). Compared to healthy controls, patients scored lower on CHQ subscales role functioning-physical and general health. Parents reported less favorable scores on the behavior subscale than adolescents. Fewer diabetes-specific family conflicts were associated with better psychosocial well-being and less depressive symptoms. Living in a one-parent family, being member of an ethnic minority and reporting lower well-being were all associated with higher HbA(1c )values. CONCLUSION: Overall, adolescents with type 1 diabetes report optimal well-being and parent report is in accordance with these findings. Poor glycemic control is common, with single-parent families and ethnic minorities particularly at risk. High HbA(1c )values are related to lower social and family functioning

A Bayesian network approach to study host and viral genetic correlates of HIV-1 disease progression

HIV disease progression is very variable among infected patients. Using classical statistical methods based on a selected number of markers, Casado et al [1] identified a number of host and viral genetic correlates for the clinical definitions of HIV-1 disease progression: elite controllers, long term non progressors including viremic controllers and clinical non progressors, regular progressors and rapid progressors.S

Evaluatie doorstroomprogramma’s mbo-pabo Amsterdam, Den Haag en Rotterdam

Sinds de invoering van toelatingstoetsen voor de pabo (2015-2016) is de doorstroom van mbo-4 studenten (met een niet-verwante opleiding) naar de pabo gestagneerd (Bussemaker, 2017). Om deze reden zijn in Den Haag, Rotterdam en Amsterdam doorstroomprogramma’s ontwikkeld om de doorstroom van mbo-4 studenten naar de pabo te verbeteren. Dat roept de vraag op in hoeverre met deze doorstroomprogramma’s de beoogde doelen behaald worden en welke factoren hierin bepalend zijn. In opdracht van de drie projectgroepen die verantwoordelijk zijn voor deze doorstroomprogramma’s heeft Het Kenniscentrum Onderwijs en Opvoeding van de Hogeschool van Amsterdam een beleidsevaluatie uitgevoerd van de doorstroomprogramma’s. Dit is een samenwerking tussen het Lectoraat Kansrijke Schoolloopbanen in een Diverse Stad en het Lectoraat Leren en Innoveren

Interleukin-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells

Lung epithelial cells contribute to local inflammation by the production of pro-inflammatory mediators like interleukin (IL)-8 and IL-6. Although their production depends on gene transcription, previous studies showed that post-transcriptional mechanisms modulate IL-8 and IL-6 production. Human lung epithelial cells turn from normoresponsive into hyperresponsive IL-8 – and IL-6–producing cells when their IL-8 and IL-6 mRNA degradation is reduced. We hypothesized that IL-17, a mediator predominantly released by memory T cells and present in airways of individuals with asthma, would modulat

Cytoskeletal architecture differentially controls post-transcriptional processing of IL-6 and IL-8 mRNA in airway epithelial-like cells

Airway epithelial cells are critically dependent on an intact cytoskeleton for innate defense functions. There are various pathophysiological conditions that affect the cytoskeletal architecture. We studied the effect of cytoskeletal distortion in polarized airway epithelial-like NCI-H292 cells on inflammatory gene expression, exemplified by interleukin(IL)-6 and IL-8. Disruption of microtubule structure with vinblastin and of actin with cytochalasin D did not affect TNF-alpha-induced IL-6 and IL-8 gene transcription but stabilized IL-8 and IL-6 mRNA. In line with previous studies, IL-8 mRNA stabilization was paralleled by hyperresponsive IL-8 production, but surprisingly, IL-6 production was reduced despite IL-6 mRNA stabilization. Polysome profiling revealed that, in cells with a disrupted cytoskeleton, translational efficiency of IL-6 mRNA was reduced, whereas that of IL-8 mRNA remained unaffected. Our findings indicate that distortion of the cytoskeleton in airway epithelial cells differentially affects both degradation and translation of IL-6 and IL-8 mRNA, modifying inflammatory gene expression and thus their innate defense functio