IL-20 is epigenetically regulated in NSCLC and down regulates the expression of VEGF

Background IL-20 is a pleiotrophic member of the IL-10 family and plays a role in skin biology and the development of haematopoietic cells. Recently, IL-20 has been demonstrated to have potential anti-angiogenic effects in non-small cell lung cancer (NSCLC) by down regulating COX-2. Methods The expression of IL-20 and its cognate receptors (IL-20RA/B and IL-22R1) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of this family was examined in normal bronchial epithelial and NSCLC cell lines. Furthermore, the effect of IL-20 on VEGF family members was examined. Results The expression of IL-20 and its receptors are frequently dysregulated in NSCLC. IL-20RB mRNA was significantly elevated in NSCLC tumours (p < 0.01). Protein levels of the receptors, IL-20RB and IL-22R1, were significantly increased (p < 0.01) in the tumours of NSCLC patients. IL-20 and its receptors were found to be epigenetically regulated through histone post-translational modifications and DNA CpG residue methylation. In addition, treatment with recombinant IL-20 resulted in decreased expression of the VEGF family members at the mRNA level. Conclusions This family of genes are dysregulated in NSCLC and are subject to epigenetic regulation. Whilst the anti-angiogenic properties of IL-20 require further clarification, targeting this family via epigenetic means may be a viable therapeutic option in lung cancer treatment. © 2011 Elsevier Ltd. All rights reserved.

The p38 mitogen-activated protein kinase regulates interleukin-1beta-induced IL-8 expression via an effect on the IL-8 promoter in intestinal epithelial cells

Several lines of evidence implicate the p38 mitogen-activated protein kinase (p38 MAPK) in the proinflammatory response to bacterial agents and cytokines. Equally, the transcription factor, nuclear factor (NF)-kappaB, is recognized to be a critical determinant of the inflammatory response in intestinal epithelial cells (IECs). However, the precise inter-relationship between the activation of p38 MAPK and activation of the transcription factor NF-kappaB in the intestinal epithelial cell (IEC) system, remains unknown. Here we show that interleukin (IL)-1beta activates all three MAPKs in Caco-2 cells. The production of IL-8 and monocyte chemotactic protein 1 (MCP-1) was attenuated by 50% when these cells were preincubated with the p38 MAPK inhibitor, SB 203580. Further investigation of the NF-kappaB signalling system revealed that the inhibitory effect was independent of the phosphorylation and degradation of IkappaBalpha, the binding partner of NF-kappaB. This effect was also independent of the DNA binding of the p65 Rel A subunit, as well as transactivation, determined by an NF-kappaB luciferase construct, using both SB 203580 and dominant-negative p38 MAPK. Evaluation of IL-8 and MCP-1 RNA messages by reverse transcription-polymerase chain reaction (RT-PCR) revealed that the inhibitory effect of SB 203580 was associated with a reduction in this parameter. Using an IL-8-luciferase promoter construct, an effect of p38 upon its activation by both pharmacological and dominant-negative p38 construct co-transfection was demonstrated. It is concluded that p38 MAPK influences the expression of chemokines in intestinal epithelial cells, through an effect upon the activation of the chemokine promoter, and does not directly involve the activation of the transcription factor NF-kappaB

Le infrastrutture viarie dismesse o declassate ed il progetto di paesaggio

Paesaggio ed infrastrutture viarie sono un binomio molto forte: il primo ha insito il concetto di accessibilità, in quanto non può esistere senza la presenza di un osservatore; la strada, invece, trova i fattori che la connotano nel suo rapporto con la morfologia su cui insiste. Le infrastrutture viarie sono elemento strutturale e strutturante non solo di un territorio, ma anche di un paesaggio. Le attuali esigenze di mobilità portano oggi a ripensare ed adeguare molte infrastrutture viarie: laddove è possibile si potenziano le strutture esistenti, in diversi casi si ricorre a nuovi tracciati o a varianti di percorso. Porsi il problema di conservare itinerari testimoni della cultura materiale ed economica di una società implica considerazioni articolate, che travalicano i limiti del sedime: una via è un organismo più complesso della semplice linea di trasporto in quanto implica tutta una serie di manufatti a supporto della mobilità e soprattutto il corridoio infrastrutturale che genera e caratterizza, ovvero una porzione variabile di territorio definita sia dal tracciato che dalla morfologia del contesto. L’evoluzione dei modelli produttivi ed economici, che oggi porta quote sempre maggiori di popolazione a passare un tempo sempre minore all’interno del proprio alloggio, rende la riflessione sulle infrastrutture viarie dismesse o declassate occasione per la progettazione di spazi per l’abitare collettivo inseriti in contesti paesaggistici, tanto urbani che rurali, tramite reti di percorsi pensate per assorbire tagli di mobilità specifici e peculiari. Partendo da queste riflessioni la Tesi si articola in: Individuazioni del contesto teorico e pratico: Lo studio mette in evidenza come la questione delle infrastrutture viarie e del loro rapporto con il paesaggio implichi riflessioni incrociate a diversi livelli e tramite diverse discipline. La definizione dello spazio fisico della strada passa infatti per la costruzione di un itinerario, un viaggio che si appoggia tanto ad elementi fisici quanto simbolici. La via è un organismo complesso che travalica il proprio sedime per coinvolgere una porzione ampia di territorio, un corridoio variabile ed articolato in funzione del paesaggio attraversato. Lo studio propone diverse chiavi di lettura, mettendo in luce le possibili declinazioni del tema, in funzione del taglio modale, del rapporto con il contesto, del regime giuridico, delle implicazioni urbanistiche e sociali. La mobilità dolce viene individuata quale possibile modalità di riuso, tutela e recupero, del patrimonio diffuso costituito dalle diversi reti di viabilità. Antologia di casi studio: Il corpo principale dello studio si basa sulla raccolta, analisi e studio dello stato dell’arte nel settore; gli esempi raccolti sono presentati in due sezioni: la prima dedicata alle esperienze più significative ed articolate, che affrontano il recupero delle infrastrutture viarie a più livelli ed in modo avanzato non concentrandosi solo sulla conversione del sedime, ma proponendo un progetto che coinvolga tutto il corridoio attraversato dall’infrastruttura; la seconda parte illustra la pratica corrente nelle diverse realtà nazionali, ponendo in evidenza similitudini e differenze tra i vari approcci.

Integrating information literacy into higher education curricula : an IL curricular integration model

This study investigates a way to systematically integrate information literacy (IL) into an undergraduate academic programme and develops a model for integrating information literacy across higher education curricula. Curricular integration of information literacy in this study means weaving information literacy into an academic curriculum. In the associated literature, it is also referred to as the information literacy embedding approach or the intra-curricular approach. The key findings identified from this study are presented in 4 categories: the characteristics of IL integration; the key stakeholders in IL integration; IL curricular design strategies; and the process of IL curricular integration. Three key characteristics of the curricular integration of IL are identified: collaboration and negotiation, contextualisation and ongoing interaction with information. The key stakeholders in the curricular integration of IL are recognised as the librarians, the course coordinators and lecturers, the heads of faculties or departments, and the students. Some strategies for IL curricular design include: the use of IL policies and standards in IL curricular design; the combination of face to face and online teaching as an emerging trend; the use of IL assessment tools which play an important role in IL integration. IL can be integrated into the intended curriculum (what an institution expects its students to learn), the offered curriculum (what the teachers teach) and the received curriculum (what students actually learn). IL integration is a process of negotiation, collaboration and the implementation of the intended curriculum. IL can be integrated at different levels of curricula such as: institutional, faculty, departmental, course and class curriculum levels. Based on these key findings, an IL curricular integration model is developed. The model integrates curriculum, pedagogy and learning theories, IL theories, IL guidelines and the collaboration of multiple partners. The model provides a practical approach to integrating IL into multiple courses across an academic degree. The development of the model was based on the IL integration experiences of various disciplines in three universities and the implementation experience of an engineering programme at another university; thus it may be of interest to other disciplines. The model has the potential to enhance IL teaching and learning, curricular development and to implement graduate attributes in higher education. Sociocultural theories are applied to the research process and IL curricular design of this study. Sociocultural theories describe learning as being embedded within social events and occurring as learners interact with other people, objects, and events in a collaborative environment. Sociocultural theories are applied to explore how academic staff and librarians experience the curricular integration of IL; they also support collaboration in the curricular integration of IL and the development of an IL integration model. This study consists of two phases. Phase I (2007) was the interview phase where both academic staff and librarians at three IL active universities were interviewed. During this phase, attention was paid specifically to the practical process of curricular integration of IL and IL activity design. Phase II, the development phase (2007-2008), was conducted at a fourth university. This phase explores the systematic integration of IL into an engineering degree from Year 1 to Year 4. Learning theories such as sociocultural theories, Bloom’s Taxonomy and IL theories are used in IL curricular development. Based on the findings from both phases, an IL integration model was developed. The findings and the model contribute to IL education, research and curricular development in higher education. The sociocultural approach adopted in this study also extends the application of sociocultural theories to the IL integration process and curricular design in higher education.

Il percorso Ciclabile cantonale della Valle Maggia (Maggia Valley Cantonal Cycleway)

La ferrovia della Valle Maggia, in Canton Ticino, ha operato tra il 1905 ed il 1965 collegando Locarno, sul Verbano, a Bignasco. Il tracciato prevedeva un armamento a scartamento ridotto; il servizio era operato con vetture automotrici dotate di giardiniera o rimorchio per le merci.

Le vie dell'Impero. Le strade coloniali italiane e il loro rapporto con la manualistica del Ventennio

Imperial roads. The Italian colonial routes and their relationship with 1920-40 manuals

IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms

Interleukin(IL)-18 is a pleiotrophic cytokine with functions in immune modulation, angiogenesis and bone metabolism. In this study, the potential of IL-18 as an immunotherapy for prostate cancer (PCa) was examined using the murine model of prostate carcinoma, RM1 and a bone metastatic variant RM1(BM)/B4H7-luc. RM1 and RM1(BM)/B4H7-luc cells were stably transfected to express bioactive IL-18. These cells were implanted into syngeneic immunocompetent mice, with or without an IL-18-neutralising antibody (αIL-18, SK113AE4). IL-18 significantly inhibited the growth of both subcutaneous and orthotopic RM1 tumors and the IL-18 neutralizing antibody abrogated the tumor growth-inhibition. In vivo neutralization of interferon-gamma (IFN-γ) completely eliminated the anti-tumor effects of IL-18 confirming an essential role of IFN-γ as a down-stream mediator of the anti-tumor activity of IL-18. Tumors from mice in which IL-18 and/or IFN-γ was neutralized contained significantly fewer CD4+ and CD8+ T cells than those with functional IL-18. The essential role of adaptive immunity was demonstrated as tumors grew more rapidly in RAG1−/− mice or in mice depleted of CD4+ and/or CD8+ cells than in normal mice. The tumors in RAG1−/− mice were also significantly smaller when IL-18 was present, indicating that innate immune mechanisms are involved. IL-18 also induced an increase in tumor infiltration of macrophages and neutrophils but not NK cells. In other experiments, direct injection of recombinant IL-18 into established tumors also inhibited tumor growth, which was associated with an increase in intratumoral macrophages, but not T cells. These results suggest that local IL-18 in the tumor environment can significantly potentiate anti-tumor immunity in the prostate and clearly demonstrate that this effect is mediated by innate and adaptive immune mechanisms.

Antenatal ureaplasma infection impairs development of the fetal ovine gut in an IL-1-dependent manner

Ureaplasma infection of the amniotic cavity is associated with adverse postnatal intestinal outcomes. We tested whether interleukin-1 (IL-1) signaling underlies intestinal pathology following ureaplasma exposure in fetal sheep. Pregnant ewes received intra-amniotic injections of ureaplasma or culture media for controls at 3, 7, and 14 d before preterm delivery at 124 d gestation (term 150 d). Intra-amniotic injections of recombinant human interleukin IL-1 receptor antagonist (rhIL-1ra) or saline for controls  were given 3 h before and every 2 d after Ureaplasma injection. Ureaplasma exposure caused fetal gut inflammation within 7 d with damaged villus epithelium and gut barrier loss. Proliferation, differentiation, and maturation of enterocytes were significantly reduced after 7 d of ureaplasma exposure, leading to severe villus atrophy at 14 d. Inflammation, impaired development and villus atrophy of the fetal gut was largely prevented by intra-uterine rhIL-1ra treatment. These data form the basis for a clinical understanding of the role of ureaplasma in postnatal intestinal pathologies.

Cytokine synthesis by intestinal intraepithelial lymphocytes. Both gamma/delta T cell receptor-positive and alpha/beta T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-gamma and IL-5

Murine intestinal intraepithelial lymphocytes (IEL) have been shown to contain subsets of alpha/beta TCR+ and gamma/delta TCR+ T cells that spontaneously produce cytokines such as IFN-gamma and IL-5. We have now determined the nature and cell cycle stage of these cytokine-producing T lymphocytes in EIL by using IFN-gamma- and IL-5-specific ELISPOT assay, cytokine-specific mRNA-cDNA dot-blot hybridization and polymerase chain reaction, and flow cytometry (FACS) for DNA analysis. When CD3+ T cells from IEL of normal C3H/HeN mice were separated into low and high density fractions by discontinuous Percoll gradients, IFN-gamma and IL-5 spot-forming cells were only found in the former population. Analysis of mRNA for these cytokines by both IFN-gamma- and IL-5-specific dot-blot hybridization and polymerase chain reaction revealed that higher levels of message for IFN-gamma and IL-5 were also seen in the low density fraction. However, cell cycle analysis of these two fractions by FACS using propidium iodide showed a similar pattern of cell cycle stages in both low and high density populations (G0 + G1 approximately 96 to 98% and S/G2 + M approximately 2 to 4%). Finally, mRNA from gamma/delta TCR+ and alpha/beta TCR+ T cells in both low and high density fractions of IEL were analyzed for IFN-gamma and IL-5 message by polymerase chain reaction. After 35 cycles of amplification, both gamma/delta TCR+ and alpha/beta TCR+ T cells in the low density fraction expressed higher levels of message for these two cytokines when compared with the high density population. These results have now shown that both gamma/delta and alpha/beta TCR+ IEL can be separated into low and high density subsets and both fractions possess a similar stage of cell cycle. However, only the low density cells (in G1 phase) of both gamma/delta and alpha/beta TCR types possess increased cytokine-specific mRNA and produce the cytokines IFN-gamma and IL-5. Our results suggest that alpha/beta TCR+ and gamma/delta TCR+ IEL can produce cytokines without cell proliferation.

Constitutive production of IL-13 promotes early-life Chlamydia respiratory infection and allergic airway disease

Deleterious responses to pathogens during infancy may contribute to infection and associated asthma. Chlamydia respiratory infections in early life are common causes of pneumonia and lead to reduced lung function and asthma. We investigated the role of interleukin-13 (IL-13) in promoting early-life Chlamydia respiratory infection, infection-induced airway hyperresponsiveness (AHR), and severe allergic airway disease (AAD). Infected infant Il13−/− mice had reduced infection, inflammation, and mucus-secreting cell hyperplasia. Surprisingly, infection of wild-type (WT) mice did not increase IL-13 production but reduced IL-13Rα2 decoy receptor levels compared with sham-inoculated controls. Infection of WT but not Il13−/− mice induced persistent AHR. Infection and associated pathology were restored in infected Il13−/− mice by reconstitution with IL-13. Stat6−/− mice were also largely protected. Neutralization of IL-13 during infection prevented subsequent infection-induced severe AAD. Thus, early-life Chlamydia respiratory infection reduces IL-13Rα2 production, which may enhance the effects of constitutive IL-13 and promote more severe infection, persistent AHR, and AAD.

The duration of Chlamydia muridarum genital tract infection and associated chronic pathological changes are reduced in IL-17 knockout mice but protection is not increased further by immunization

IL-17 is believed to be important for protection against extracellular pathogens, where clearance is dependent on neutrophil recruitment and local activation of epithelial cell defences. However, the role of IL-17 in protection against intracellular pathogens such as Chlamydia is less clear. We have compared (i) the course of natural genital tract C. muridarum infection, (ii) the development of oviduct pathology and (iii) the development of vaccine-induced immunity against infection in wild type (WT) BALB/c and IL-17 knockout mice (IL-17-/-) to determine if IL-17-mediated immunity is implicated in the development of infection-induced pathology and/or protection. Both the magnitude and duration of genital infection was significantly reduced in IL-17-/- mice compared to BALB/c. Similarly, hydrosalpinx was also greatly reduced in IL-17-/- mice and this correlated with reduced neutrophil and macrophage infiltration of oviduct tissues. Matrix metalloproteinase (MMP) 9 and MMP2 were increased in WT oviducts compared to IL-17-/- animals at day 7 post-infection. In contrast, oviducts from IL-17-/- mice contained higher MMP9 and MMP2 at day 21. Infection also elicited higher levels of Chlamydia-neutralizing antibody in serum of IL-17-/- mice than WT mice. Following intranasal immunization with C. muridarum Major Outer Membrane Protein (MOMP) and cholera toxin plus CpG adjuvants, significantly higher levels of chlamydial MOMP-specific IgG and IgA were found in serum and vaginal washes of IL-17-/- mice. T cell proliferation and IFNγ production by splenocytes was greater in WT animals following in vitro re-stimulation, however vaccination was only effective at reducing infection in WT, not IL-17-/- mice. Intranasal or transcutaneous immunization protected WT but not IL-17-/- mice against hydrosalpinx development. Our data show that in the absence of IL-17, the severity of C. muridarum genital infection and associated oviduct pathology are significantly attenuated, however neither infection or pathology can be reduced further by vaccination protocols that effectively protect WT mice.