Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes
Ratter, Jacqueline M. ; Rooijackers, Hanne M.M. ; Hooiveld, Guido J. ; Hijmans, Anneke G.M. ; Galan, Bastiaan E. de; Tack, Cees J. ; Stienstra, Rinke - \ 2018
Frontiers in Immunology 9 (2018). - ISSN 1664-3224
cytokines - glycolysis - immunometabolism - innate immune cells - lactate - monocytes

Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands in vitro, indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans in vivo increased ex vivo glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate ex vivo, reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti-inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses.

Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis
Lachmandas, Ekta ; Rios-Miguel, Ana B. ; Koeken, Valerie A.C.M. ; Pasch, Eva van der; Kumar, Vinod ; Matzaraki, Vasiliki ; Li, Yang ; Oosting, Marije ; Joosten, Leo A.B. ; Notebaart, Richard A. ; Noursadeghi, Mahdad ; Netea, Mihai G. ; Crevel, Reinout van; Pollara, Gabriele - \ 2018
The Journal of Infectious Diseases 218 (2018)1. - ISSN 0022-1899 - p. 165 - 170.
cytokines - functional genomics - human challenge model - immune response - immunometabolism - metabolism - microarrays - transcriptomics - tuberculosis

Cellular metabolism can influence host immune responses to Mycobacterium tuberculosis. Using a systems biology approach, differential expression of 292 metabolic genes involved in glycolysis, glutathione, pyrimidine, and inositol phosphate pathways was evident at the site of a human tuberculin skin test challenge in patients with active tuberculosis infection. For 28 metabolic genes, we identified single nucleotide polymorphisms that were trans-acting for in vitro cytokine responses to M. tuberculosis stimulation, including glutathione and pyrimidine metabolism genes that alter production of Th1 and Th17 cytokines. Our findings identify novel therapeutic targets in host metabolism that may shape protective immunity to tuberculosis.

In vitro fermentation and immunomodulating characteristics of dietary fibres
Rösch, C. - \ 2016
Wageningen University. Promotor(en): Harry Gruppen; Henk Schols. - Wageningen : Wageningen University - ISBN 9789462577954 - 130 p.
dietary fibres - degradation - enzymes - immunomodulatory properties - cytokines - glycosides - fermentation - voedingsvezels - degradatie - enzymen - immunomodulerende eigenschappen - cytokinen - glycosiden - fermentatie


Dietary fibres are a diverse group of substances, indigestible by human digestive enzymes, but (partially) fermentable in the human large intestine by the resident microbiota. Many health beneficial effects of fibres such as lowering blood cholesterol levels or increasing stool bulk have been reported. For some fibres, immunomodulating properties have been shown. Other studies investigate the degradation fate of fibres by the bacteria. In this PhD thesis BMDCs from TLR2/4 knock out mice were validated to be unresponsive to naturally present contaminants like LPS and proved to be a good tool to analyse the immune response of dietary fibres. A variety of 44 fibres, was tested on these immune cells and all fibres were found to modulated the immune system differently. Also, different immunomodulating properties of an oat and barley β-glucan having rather similar chemical structures, were found. The insoluble fraction of the β-glucans induced highest amounts of cytokines. As a consequence, sample preparation such as drying, dispersing and heating were shown to affect the immunomodulatory properties. The in vitro fermentation characteristics of barley β-glucan and sugar beet pectin and the immunomodulatory properties of their degradation products on BMDCs were compared and shown to be substrate and degradation product specific. This study showed, that glycosidic degradation products of both fibres induced higher amounts of cytokines than their intact polysaccharide. An in vitro batch fermentation of soluble, indigestible maltodextrins by human faecal inocula was monitored and the activity of carbohydrate degrading enzymes, produced by the microbiota, was analysed. Results revealed that the maltodextrin was only slowly and incompletely fermented, despite the high potential of microbial enzymes present to degrade typical starch linkages.

Overall, this thesis showed that dietary fibres interact and influence the immune system dependent on their individual chemical fine structure. Additionally, an evaluation of the health impact of dietary fibres can only be complete when also glycosidic fermentation products are considered.

Plant Biotechnology meets Immunology : plant-based expression of immunologically relevant proteins
Wilbers, R.H.P. - \ 2015
Wageningen University. Promotor(en): Jaap Bakker, co-promotor(en): Arjen Schots; Geert Smant. - Wageningen : Wageningen University - ISBN 9789462574335 - 229
plantenbiotechnologie - immunologie - planten - eiwitten - farmaceutische eiwitten - interleukine 10 - ontstekingsremmers - biologische activiteit - cytokinen - genexpressie - transforming growth factor - wormen - recombinant eiwitten - glycoproteïnen - plant biotechnology - immunology - plants - proteins - pharmaceutical proteins - interleukin 10 - antiinflammatory agents - biological activity - cytokines - gene expression - helminths - recombinant proteins - glycoproteins

The incidence of inflammatory disorders in industrialized countries has dramatically increased over the last decennia, which is believed to result from a change in life-style. Treatment of these inflammatory disorders relies on the intervention in immune responses thereby restoring homeostasis. For now, many inflammatory disorders are treated with broad-acting immunosuppressive drugs or monoclonal antibodies that specifically target pro-inflammatory molecules of the immune system. An alternative therapeutic approach would be to use immunomodulatory proteins that are naturally involved in re-establishing immune homeostasis. This thesis describes the plant-based expression of a variety of immunomodulatory cytokines that may be used as biopharmaceutical proteins in the future. Furthermore, this thesis contains a pioneering chapter on the plant-based expression of immunomodulatory helminth-secreted glycoproteins.

In Chapter 2 we describe the plant-based expression of the immune-regulatory cytokine human transforming growth factor β1 (TGF-β1). By co-expressing human furin with latent TGF-β1 we were able to engineer the post-translational proteolytic processing of TGF-β1, which enabled the production of biologically active TGF-β1. In Chapter 3 we reveal that aggregation is a major production bottleneck for the anti-inflammatory cytokine interleukin-10 (IL-10). By protein engineering we were able to prevent aggregation and created a biologically active fusion protein of IL-10. In Chapter 4 we express biologically active IL-22 in plants. We reveal that, in contrast to current literature, its activity is independent of the presence of N-glycans or their composition. This chapter further reveals that plants offer a powerful tool to allow investigation into the role of N-glycans in protein folding and biological activity of glycoproteins. In Chapter 5 we further explore the potential of glyco-engineering in plants by engineering helminth-like N-glycans. We produce large quantities of two major egg antigens from Schistosoma mansoni and successfully engineer Lewis X, LDN and LDNF N-glycan structures. These plant biotechnological research lines are a showcase for the potential of engineering proteins as well as post-translational modifications in plants with special emphasis on N-glycan engineering. Altogether, the results presented in the first four chapters reveal the remarkable flexibility of plants as a production platform for recombinant proteins. It showcases the potential of engineering proteins as well as post-translational modifications in plants, but it especially highlights the engineering of tailor made N-glycans in plants. This, combined with the speed of transient expression by means of agroinfiltration, makes transient expression in Nicotiana benthamiana a powerful tool to study the role of N-glycans on glycoprotein function.

In parallel to these plant biotechnological research lines, we also developed an in vitro model system based on mouse bone marrow-derived cells to study immunological responses. We used this model to obtain clues on why IL-10 therapy has not been as successful as previously anticipated. In Chapter 6 we have set-up biological activity assays based on bone marrow-derived cells and reveal that IL-10 activity is dependent on both IL-10R1 and IL-10R2, but not IL-10R2-associated signalling via Tyk2. We also show that interactions between IL-10R1 and IL-10R2 (both intracellular and extracellular) reduce cellular binding of IL-10, but are crucial to initiate IL-10 mediated signalling. Furthermore, we observed that macrophages and dendritic cells respond differently to IL-10. This was further investigated in Chapter 7 where we reveal that GM-CSF (the cytokine used to differentiate dendritic cells) is responsible for negatively regulating early IL-10-mediated responses. Strikingly, GM-CSF does not strongly affect the IL-10-induced activation of the transcription factor STAT3. Instead, GM-CSF induces strong constitutive phosphorylation of GSK-3β, a signalling component downstream of the PI3K/Akt pathway. These immunological chapters give novel insights on the mechanism of initiating IL-10-induced signalling and on the possible integration of signal transduction pathways elicited by different cytokines. Ultimately this knowledge could provide us with new therapeutic strategies to treat inflammatory disorders.

Lung pathogenicity of European genotype 3 strain porcine reproductive and respiratory syndrome virus (PRRSV) differs from that of subtype 1 strains.
Weesendorp, E. ; Rebel, J.M.J. ; Popma-de Graaf, D.J. ; Fijten, H.P.D. ; Stockhofe, N. - \ 2014
Veterinary Microbiology 174 (2014)1-2. - ISSN 0378-1135 - p. 127 - 138.
experimentally infected-pigs - lelystad virus - immunological responses - immune-responses - swine - cells - disease - expression - cytokines - virulence
Porcine reproductive and respiratory syndrome (PRRS) is difficult to control due to a high mutation rate of the PRRS virus (PRRSV) and the emergence of virulent strains. The objective of this study was to analyse early and late pathological responses in the respiratory tract after infection with the European PRRSV subtype 3 strain Lena in comparison to two European PRRSV subtype 1 strains: Belgium A and Lelystad-Ter Huurne (LV). For each virus strain, groups of twelve pigs were inoculated, and four pigs per group were euthanized at days 3, 7 and 35 post-infection (p.i.) for consecutive examination. Infection with strain Lena resulted in a more severe disease than with the subtype 1 strains, an inflammatory response within the first week of infection with expression of IL-1a in the lung and lymph node, and an influx of neutrophils and monocytes in bronchoalveolar lavage fluid (BALF). Infection with strain Belgium A or LV resulted in mild or no pathology within the first week of infection, but inflammatory cell influx in the lung interstititium was increased at the end of the experiment at day 35 p.i. At five weeks p.i., all strains induced a higher percentage of cytotoxic T cells and higher levels of IFN-¿ producing cells in BALF. This might have contributed to clearance of virus. In general, subtype 3 strain Lena induced a stronger early inflammatory response which led to more severe clinical disease and pathology. On the other hand, this may have supported an enhanced or faster clearance of virus in tissues, compared to subtype 1 strains.
Activated complement factor 3 is associated with liver fat and liver enzymes: the CODAM study
Wlazlo, N. ; Greevenbroek, M.M.J. van; Ferreira, I. ; Jansen, E.H.J.M. ; Feskens, E.J.M. ; Kallen, C.J.H. van der; Schalkwijk, C.G. ; Bravenboer, B. ; Stehouwer, C.D.A. - \ 2013
European Journal of Clinical Investigation 43 (2013)7. - ISSN 0014-2972 - p. 679 - 688.
insulin-resistance - nonalcoholic steatohepatitis - alanine aminotransferase - medical progress - adipose-tissue - disease - c3 - mice - cytokines - protein
Background The complement system may be involved in the pathogenesis of alcoholic and nonalcoholic liver disease, although studies in humans are scarce. For this reason, we investigated whether circulating levels of activated complement factor 3 (C3a) were associated with hepatic steatosis and hepatocellular damage. Materials and methods Plasma C3a, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were determined in 523 individuals (61% men, age 59 ± 7 years). Liver enzymes (LEs) were standardized and compiled into a LE score. Liver fat content was estimated using a predictive equation that has recently been validated with magnetic resonance spectrometry. Cross-sectional associations between C3a and liver fat or LE s were investigated with multiple linear regression analyses, stratified in no-to-moderate vs. heavy alcohol consumers (men: > 30 g/day; women: > 20 g/day). Results C3a was associated with liver fat percentage both in the no-to-moderate (ß = 0·223; 95%CI 0·036; 0·409) and in the heavy alcohol consumers (ß = 0·632; 95%CI 0·259–1·004; P-interaction = 0·047). C3a was also associated with the LE score in heavy alcohol consumers (ß = 0·917; 95%CI 0·443–1·392), but not in no-to-moderate alcohol consumers (ß = 0·042; 95%CI -0·198 to 0·281; P-interaction = 0·001). Conclusions C3a levels, as a marker of complement activation, were associated with liver fat content and hepatocellular injury, at least in subjects who consume considerable amounts of alcohol daily.
Comparative analysis of immune responses following experimental infection of pigs with European porcine reproductive and respiratory syndrome virus strains of differing virulence
Weesendorp, E. ; Morgan, S. ; Stockhofe-Zurwieden, N. ; Popma-de Graaf, D.J. ; Graham, S.P. ; Rebel, J.M.J. - \ 2013
Veterinary Microbiology 163 (2013)1-2. - ISSN 0378-1135 - p. 1 - 12.
classical swine-fever - immunological responses - circovirus type-2 - t-lymphocytes - syndrome prrs - cells - disease - expression - antibodies - cytokines
Porcine reproductive and respiratory syndrome virus (PRRSV) is difficult to control due to a high mutation rate and the emergence of virulent strains. The objective of this study was to analyze the immunological and pathological responses after infection with the European subtype 3 strain Lena in comparison to subtype 1 strains Belgium A and Lelystad-Ter Huurne (LV). Sixteen pigs were inoculated per strain, and sixteen pigs with PBS. At days 7 and 21 post-inoculation (p.i.), four pigs per group were immunized with an Aujeszky disease vaccine (ADV) to study the immune competence after PRRSV infection. Infection with the Lena strain resulted in fever and clinical signs. This was not observed in the Belgium A or LV-infected pigs. Infection with the Lena strain resulted in high virus titers in serum, low numbers of IFN-¿ secreting cells, a change in leukocyte populations and a delayed antibody response to immunization with ADV. Levels of IL-1ß, IFN-a, IL-10, IL-12, TNF-a and IFN-¿ mRNA of the Lena-infected pigs were increased during the first week of infection. For pigs infected with the Belgium A or LV strain, the effects of infection on these parameters were less pronounced, although for the Belgium A-infected pigs, the level of the analyzed cytokines, except for TNF-a, and leukocyte populations were comparable to the Lena-infected pigs. These results suggest that while the outcome of infection for the three strains was comparable, with mostly clearance of viremia at day 33 p.i, differences in immune responses were observed, perhaps contributing to their virulence.
Culicoides obsoletus allergens for diagnosis of insect bite hypersensitivity in horses
Meide, N.M.A. van der - \ 2013
Wageningen University. Promotor(en): Huub Savelkoul, co-promotor(en): Edwin Tijhaar. - S.l. : s.n. - ISBN 9789461736697 - 228
paarden - equus - culicoides obsoletus - insectenbeten - allergenen - overgevoeligheid - allergieën - cytokinen - diagnose - elisa - vectoren, ziekten - immunologie - horses - insect bites - allergens - hypersensitivity - allergies - cytokines - diagnosis - disease vectors - immunology

AInsect Bite Hypersensitivity (IBH) is the most common skin allergy in horses and involves a Type I (IgE mediated) hypersensitivity reaction against bites of insects, mainly of the Culicoides species. Welfare of affected horses is seriously reduced and no fully curative treatment is yet available. Furthermore, current diagnostic tests are unreliable because of their low sensitivity and specificity. Aim of our research was to increase the understanding of immunological aspects of IBH, with special attention to improving diagnosis by the characterization and production of recombinant allergens.

Whole body extracts (WBE) of three Culicoides species: C. obsoletus C. nubeculosus and C. sonorensis were evaluated for their applicability for diagnosis of IBH in horses in The Netherlands. They were tested for IgE binding by ELISA and Western blotting and for their capacity to degranulate basophils in a histamine release test. For all tests, best results were obtained with C. obsoletus. The ELISA was further evaluated using C. obsoletus extract on approximately 200 IBH affected and healthy horses, which demonstrated high test sensitivity and specificity. C. obsoletus-specific IgE serum levels were found to be the same in the IBH season and off season, suggesting that the test can be used to diagnose horses in winter when clincial symptoms are absent.

Since C. obsoletus was found to be the most important species for diagnosis of IBH in The Netherlands, mRNA of this Culicoides species was sequenced and assembled to create a transcriptome. Using the sequences from in literature described allergens from C. nubeculosus and C. sonorensis, similarity searches were performed on this transcriptome,. This resulted in the identification of seven allergens from C. obsoletus. These allergens were cloned and expressed as recombinant proteins in E. coli and named Cul o 1 – Cul o 7. The frequency of positive test results by ELISA within IBH affected horses ranged from 38 % to 67 %. The capability of the allergens to induce Type I hypersensitivity reaction in IBH affected horses was demonstrated by an intradermal test.

The applicability of the 7 C. obsoletus derived recombinant allergens was further evaluated and compared with C. obsoletus WBE in an IgE ELISA using a large number of horses.The highest test accuracy was obtained with WBE, followed by Cul o 2, 3 and 5. Two ELISA’s with a combination of recombinant allergens, combi-1 (Cul o 3, 5 and 7) and combi-2 (Cul o 1, 2, 5 and 7) were additionally performed and both resulted in high test accuracies close to that obtained with WBE. Both combi-1 and combi-2 resulted in a lower test sensitivity with samples collected in winter compared to samples collected in IBH season, but most IBH affected horses could still also be correctly diagnosed in winter.

The association between several factors and IgE levels against C. obsoletus whole body extract and the 7 recombinant allergens was quantified. Furthermore, the relation between IgE levels and severity of symptoms was examined. Severity of symptoms and IgE levels against several C. obsoletus allergens were found to be related. Factors that were found to be associated with IgE levels were: breed, age, month of scoring, interaction between IBH status and month of scoring, degree of itchiness and number of seasons horses were affected with IBH.

The general discussion discussed the prospects to use the produced recombinant allergens for immunotherapy treatment of IBH affected horses. The panel of all 7 recombinant allergens allows to determine for which exact components of C. obsoletus the IBH horses are allergic (“component resolved diagnosis”). This will enable a tailor made composition of (recombinant) allergens for use in immunotherapy.

Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and electrochemiluminescense-based multi-array platform
Bussel, B.C.T. van; Ferreira, I. ; Waarenburg, M.P.H. ; Greevenbroek, M.M.J. van; Kallen, C.J.H. van der; Henry, R.M.A. ; Feskens, E.J.M. ; Stehouwer, C.D.A. ; Schalkwijk, C.G. - \ 2013
PLoS ONE 8 (2013)3. - ISSN 1932-6203 - 11 p.
coronary-artery-disease - public-health practice - low-grade inflammation - cardiovascular-disease - deming regression - atherosclerosis - risk - cytokines - markers - association
Background - In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available. Methods - We measured, in a large ongoing cohort study (n = 574), by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD) and single-biomarker techniques (ELISA or immunoturbidimetric assay), the following biomarkers of low-grade inflammation: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects’ cardiovascular risk factors by ANOVA. Results - Despite that both methods ranked individuals’ levels of biomarkers very similarly (Pearson’s r all=0.755) absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP), 0.711 (SAA), 0.895 (sICAM-1) and 0.858 (sVCAM-1). Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method. Conclusions - Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies.
Cytokinine is meer dan hormoon dat celdeling stimuleert : sturen hormoonhuishouding gecompliceerd
Heuvelink, E. ; Kierkels, T. - \ 2012
Onder Glas 9 (2012)8. - p. 28 - 29.
potplanten - sierplanten - cytokinen - plantenontwikkeling - cultuurmethoden - hormonen - groeifactoren - glastuinbouw - pot plants - ornamental plants - cytokines - plant development - cultural methods - hormones - growth factors - greenhouse horticulture
Cytokinine staat bekend als het hormoon dat celdeling stimuleert. Daar ontleent het zelfs zijn naam aan. Maar zoals alle hormonen heeft ook dit meerdere effecten, die ook nog eens worden bepaald door verhouding met andere hormonen. Vooral de balans met auxine is van belang.
Low-frequency electromagnetic fields do not alter responses of inflammatory genes and proteins in human monocytes and immune cell lines
Bouwens, M. ; Kleijn, S. de; Cuppen, J.J.M. ; Savelkoul, H.F.J. ; Verburg-van Kemenade, B.M.L. - \ 2012
Bioelectromagnetics 33 (2012)3. - ISSN 0197-8462 - p. 226 - 237.
blood mononuclear-cells - nf-kappa-b - magnetic-fields - human-lymphocytes - expression - macrophages - induction - exposure - cytokines - stimulation
The effects of low frequency electromagnetic fields (LF EMF) on human health are the subject of on-going research and serious public concern. These fields potentially elicit small effects that have been proposed to have consequences, either positive or negative, for biological systems. To reveal potentially weak but biologically relevant effects, we chose to extensively examine exposure of immune cells to two different signals, namely a complex multiple waveform field, and a 50¿Hz sine wave. These immune cells are highly responsive and, in vivo, modulation of cytokine expression responses can result in systemic health effects. Using time course experiments, we determined kinetics of cytokine and other inflammation-related genes in a human monocytic leukemia cell line, THP-1, and primary monocytes and macrophages. Moreover, cytokine protein levels in THP-1 monocytes were determined. Exposure to either of the two signals did not result in a significant effect on gene and protein expression in the studied immune cells. Also, additional experiments using non-immune cells showed no effects of the signals on cytokine gene expression. We therefore conclude that these LF EMF exposure conditions are not expected to significantly modulate innate immune signaling. Bioelectromagnetics.
Increased consumption of fatty and lean fish reduces serum c-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies
Pot, G.K. ; Geelen, A. ; Majsak-Newman, G. ; Harvey, L.J. ; Nagengast, F.M. ; Witteman, B.J.M. ; Meeberg, P.C. van de; Hart, A.R. ; Schaafsma, G. ; Lund, E.K. ; Rijkers, G.T. ; Kampman, E. - \ 2010
The Journal of Nutrition 140 (2010)2. - ISSN 0022-3166 - p. 371 - 376.
colorectal-cancer risk - multiplex immunoassay - oxidative stress - bowel-disease - cytokines - acids - plasma - carcinogenesis - validation - sample
Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA. Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (-0.5 mg/L; 95% CI -0.9, -0.2) and cod (-0.4 mg/L; 95% CI -0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish. In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.
Sustained effects of early-life oral colistin treatment on immune reactivity to intratracheally administered LPS and HuSA in chicken
Lammers, A. ; Zutphen, L.J.W. van; Vries Reilingh, G. de; Parmentier, H.K. - \ 2010
In: Proceeding of the 11th Avian Immunology Research Group Conference, Budapest, Hungary, 7-10 October 2010. - Budapest, Hungary : Diamond Congress LTd. - ISBN 9789638801920 - p. 51 - 51.
vogels - immunologie - immuniteit - b lymfocyten - interferon - receptoren - aviaire influenzavirussen - cytokinen - vaccinatie - immunogenetica - birds - immunology - immunity - b lymphocytes - receptors - avian influenza viruses - cytokines - vaccination - immunogenetics
Effects of mushroom-derived ß-glucan rich polysaccharide extracts on nitric oxide production by bone marrow-derived macrophages and nuclear factor-kB transactivation in Caco-2 reporter cells: Can effects be explained by structure?
Volman, J.J. ; Helsper, J.P.F.G. ; Wei, S. ; Baars, J.J.P. ; Griensven, L.J.L.D. van; Sonnenberg, A.S.M. ; Mensink, R.P. ; Plat, J. - \ 2010
Molecular Nutrition & Food Research 54 (2010)2. - ISSN 1613-4125 - p. 268 - 276.
tumor-necrosis-factor - agaricus-blazei murill - in-vitro - liquid culture - fungal - cytokines - antitumor - immunity - dectin-1 - alpha
Mushrooms are known for their immune-modulating and anti-tumour properties. The polysaccharide fraction, mainly -glucans, is responsible for the immune-modulating effects. Fungal -glucans have been shown to activate leukocytes, which depend on structural characteristics of -glucans. As edible mushrooms come in contact with the intestinal immune system, effects on enterocytes are also interesting. Our aim was to evaluate the effect of mushroom polysaccharide extracts varying in -glucan structure on nitric oxide production by bone marrow-derived macrophages (BMMs) from mice and on nuclear factor-B transactivation in human intestinal Caco-2 cells. We demonstrated that extracts from Agaricus bisporus stimulated nitric oxide production by BMM, whereas extracts from Coprinus comatus and spores of Ganoderma lucidum had only minor effects. Furthermore, extracts of A. blazei Murill and Phellinus linteus had no effect at all. Almost all mushroom extracts lowered nuclear factor-B transactivation in Caco-2 cells. Structural analysis of A. bisporus compared with A. blazei Murill suggests that branching of the -glucan chain is essential for immune-stimulating activity. In conclusion, extracts from A. bisporus activate BMM, without activating enterocytes. These characteristics make A. bisporus an attractive candidate as a nutritional compound to stimulate the immune response in depressed states of immunity
Locomotion and muscle mass measures in a murine model of collagen-induced arthritis
Hartog, A. ; Hulsman, J. ; Garssen, J. - \ 2009
BMC Musculoskeletal Disorders 10 (2009). - ISSN 1471-2474 - 7 p.
rheumatoid-arthritis - cachexia - methotrexate - inflammation - mechanisms - cytokines - pain - mice
Background: Rheumatoid arthritis (RA) is characterized by chronic poly-arthritis, synovial hyperplasia, erosive synovitis, progressive cartilage and bone destruction accompanied by a loss of body cell mass. This loss of cell mass, known as rheumatoid cachexia, predominates in the skeletal muscle and can in part be explained by a decreased physical activity. The murine collagen induced arthritis (CIA) model has been proven to be a useful model in RA research since it shares many immunological and pathological features with human RA. The present study explored the interactions between arthritis development, locomotion and muscle mass in the CIA model. Methods: CIA was induced in male DBA/1 mice. Locomotion was registered at different time points by a camera and evaluated by a computerized tracing system. Arthritis severity was detected by the traditionally used semi-quantitative clinical scores. The muscle mass of the hind-legs was detected at the end of the study by weighing. A methotrexate (MTX) intervention group was included to study the applicability of the locomotion and muscle mass for testing effectiveness of interventions in more detail. Results: There is a strong correlation between clinical arthritis and locomotion. The correlations between muscle mass and locomotion or clinical arthritis were less pronounced. MTX intervention resulted in an improvement of disease severity accompanied by an increase in locomotion and muscle mass. Conclusion: The present data demonstrate that registration of locomotion followed by a computerized evaluation of the movements is a simple non invasive quantitative method to define disease severity and evaluate effectiveness of therapeutic agents in the CIA model.f
Nutritional zinc deficiency, immune capacity and malaria : a study on mediators of immunity to malaria caused by Plasmodium falciparum in African children
Mbugi, E.V. - \ 2009
Wageningen University. Promotor(en): Huub Savelkoul; J.F. Shao, co-promotor(en): Hans Verhoef. - [S.l. : S.n. - ISBN 9789085855316 - 174
malaria - plasmodium falciparum - immuniteit - zink - kinderen - geneesmiddelresistentie - immuniteitsreactie - mineraaltekorten - voedingsstoffentekorten - cytokinen - antilichamen - endotheel - anemie - tropische ziekten - tanzania - immunity - zinc - children - drug resistance - immune response - mineral deficiencies - nutrient deficiencies - cytokines - antibodies - endothelium - anaemia - tropical diseases
This thesis aimed at investigating the role of genetic and nutritional factors that affect the immune response to malaria in Tanzanian children. The introductory chapter (Chapter 1) reviews the importance of nutritional deficiencies, particularly of zinc, and presents the hypothesis that such deficiencies lead to impaired immunity and contribute to the burden of malaria. The chapter also describes current efforts to prevent malaria through intermittent preventive treatment, both in infants (IPTi) and pregnant women (IPTp). Sulfadoxinepyrimethamine is still used for first-line treatment of uncomplicated malaria, or, in many countries, to prevent malaria and anaemia in pregnancy. In malaria endemic areas, development of resistance to previously valuable antimalarial drugs has been continuously reported for decades. Thus our initial longitudinal study aimed at measuring the prevalence of resistance-associated mutations on dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes (dhfr and dhps) that confer parasite resistance to sulphadoxinepyrimethamine (SP) that was used as an interim antimalarial drug after chloroquine resistance. Although SP resistance-associated point mutations were highly prevalent, we observed an adequate parasite response to SP (Chapter 2). We speculated that the impact of the dhfr and dhps mutations on SP resistance may be dependent at least in part on the protective immunity that has developed in response to frequent exposure to infection and may be weighed down by host immunity in endemic areas and thus impacts in the continued use of the drug for treatment of malaria. The impact of other drugs with similar mechanisms of action used as antibiotics in selecting mutations responsible for SP resistance needs therefore to be studied for their modulating activity of the immune response. These findings underscore the relevance to further study the crucial involvement of the immune system in the development of protection against malaria but also affecting the efficacy of treatment modalities of malaria in various African conditions.
In the subsequent cross-sectional studies, we assessed the effect of deficiencies of zinc and magnesium as well as iron deficiency anaemia on malaria-specific cytokine responses indicative of innate immunity to Plasmodium falciparum (Chapter 3). In this study, we used Plasmodium falciparum-parasitised red blood cells (pRBCs) as antigens for in vitro stimulation of peripheral blood mononuclear cells (PBMCs). Cytokines were measured in the supernatant of cultured PBMCs after 24 hours of stimulation. Zinc deficiency was associated with a marked increase in monocyte-derived TNF-α concentration in children with malarial infection but not in their uninfected peers. In children with malarial infection, iron deficiency anaemia was associated with elevated concentrations of TNF-α, whereas magnesium deficiency in children without malaria seemed to be associated with increased concentrations of IL-10. Our findings reflected plasticity in cytokine profiles of monocytes reacting to malaria infection under conditions of different nutrient deficiencies. Following the observation of the variable impact of micronutrients on innate cytokines, we evaluated the profile of both type I and type II cytokines and whether they were influenced by nutritional and malaria status (Chapter 4). The cytokine measurements were performed at day 7 of stimulation anticipating that this timing was optimal for measuring effects on these cytokines mainly derived from activated T-cells. The results indicated a variable influence of nutrient deficiencies on increased cytokine response with zinc deficiency and iron deficiency anemia having greater impact on type I and magnesium deficiency on type II cytokines. The subsequent study evaluated the plasma levels of naturally acquired antimalarial antibodies of variousIgG subclasses plus the total IgG and IgM levels and whether they were associated with zinc deficiency based on preceding chapters (Chapter 5). The results indicated a high variability in antibody levels with zinc deficiency, varying with age of the affected child. IgG3 appeared to be predominant across all age subgroups within < 5 yrs aged children providing clues that IgG3 might confer immune protection to malaria under conditions of zinc deficiency. Chapter 6 explored the association between CD36 deficiency, P. falciparum in vitro adherence on purified CD36 and anemia in children. CD36 is a receptor that occurs on the surface of activated immune cells and vascular endothelial cells and participates in phagocytosis and lipid metabolism. We hypothesized that it could play a fundamental role in cytoadherence of erythrocytes that are parasitized by Plasmodium. Our results showed that CD36 deficiency was associated with protection against the development of malarial anemia in children and that it may be mediated through reduced cytoadherence of infected red blood cells to vascular endothelium.
These studies demonstrate that despite antimalarial drug resistance, there is a potential for optimizing the immunological protective capacity in the population to confer parasite clearance that can be variably influenced by micronutrient status. Improving nutritional status in this population could be rewarding not only to increase protection to malaria but possibly also to other infections.
A multidisciplinary study of allergy : mouse models, immune modulation and lifestyle
Jeurink, P.V. - \ 2008
Wageningen University. Promotor(en): Huub Savelkoul; Gerrit Antonides, co-promotor(en): Johan van Ophem; Harry Wichers. - S.l. : S.n. - ISBN 9789085049616 - 275
allergieën - immunotherapie - levensstijl - diermodellen - antigenen - t cellen - cytokinen - immuniteitsreactie - immuniteit - immunologie - allergies - immunotherapy - lifestyle - animal models - antigens - t lymphocytes - cytokines - immune response - immunity - immunology
Allergic diseases affect a substantial part of the global population. Although extensive studies have elucidated the allergic mechanism, no conclusive answer has yet been found that will prevent the onset of an allergic disease. Literature suggests that no single factor like a gene mutation, environmental factor or lifestyle component can be hold accountable for the allergic cascade. Therefore, the main goal of this research project was to use a multidiscipli¬nary approach to allergies, by combining information on the genetic components, lifestyles and in vivo and in vitro assessment of the immune cells involved in allergy.
The accomplishment of this multidisciplinary goal required knowledge on the genetic factors involved in the immunopathology of allergic diseases, but also immunological and cell biological knowledge. In addition, we investigated the influence of environmental factors on the allergic response which also required knowledge on sociology and economics to assess involved lifestyle factors. Within the multidisciplinary research areas, allergic responses are studied at multiple levels. For example, the genetic differences can be studied by means of mice with different genetic backgrounds (BALB/c, STS/A, C57BL/6) or in knock-out (CD4 or CD8 knock-out) or transgenic (IL-5 transgenic) mice. These differences in the genetic background on their turn have an effect on the expression of the allergic disease characteristics. Examples of the assessed allergic characteristics comprise antigen-presentation by specialized antigen-presenting cells, the presence of T helper 2 cells, the involvement of Th2 produced cytokines like IL-4 and IL-5, and the isotype switching of B cells towards allergen-specific IgE. Alterations of the allergic characteristics were studied by the use of in vitro cultures of human peripheral blood mononuclear cells (PBMC) that display all above mentioned characteristics when they are properly isolated, cryopreserved and cultured. These alterations were elicited by the use of heat-treatment of allergens or the exposure to fungal derived proteins or polysaccharides. Taken together, these different levels within the allergic individual can on their turn be influenced by environmental and nutritional factors. To study this, lifestyle factors have been assessed by the use of a personalized internet-based questionnaire and these data were thereafter linked to allergen-specific immunoglobulin levels. To further stress the importance of multilevel research within a multidisciplinary study, a more detailed description of the separate chapters within this thesis are combined with their major results, and finalized with future perspectives.
A differential role for corticosteroid receptors in neuroendocrine-immune interactions in carp (Cyprinus carpio L.)
Stolte, H.H. - \ 2008
Wageningen University. Promotor(en): Huub Savelkoul; G. Flik, co-promotor(en): Lidy van Kemenade. - [S.l.] : S.n. - ISBN 9789085851998 - 231
karper - corticoïden - hormoonreceptoren - immunologie - immuniteit - immuniteitsreactie - interacties - stress - cytokinen - visteelt - neuroendocrinologie - carp - corticoids - hormone receptors - immunology - immunity - immune response - interactions - cytokines - fish culture - neuroendocrinology
In this thesis we investigated the involvement of the receptors for the stress hormone cortisol in stress and immune regulation. We set out to characterise the pro-inflammatory cytokine interferon gamma (IFN-γ). Furthermore, we used a genome wide screen (microarray) to search for additional genes that might be involved in regulation of the stress or the immune response.

In teleostean fishes cortisol can be bound by different receptors encoded by at least three different genes. An ancestral corticosteroid receptor (AncCR) is assumed to have been an effective receptor for cortisol in the ancestors of fishes. An early genomic duplication in the fish lineage, over 450 million years ago, led to separate glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) genes, both of which retained the ability to bind cortisol. A second major genomic duplication event took place only in teleostean fishes (not in other vertebrates), and gave rise to duplicate GR genes (GR1 and GR2). Even more variants developed as a result of alternative splicing of the GR1 gene which introduces a nine amino acid insert in the DNA-binding domain of GR1a, GR1b does not have this insert.

To investigate how one ligand can regulate many and very diverse functions using multiple receptors, we describe the expression of GR1 (a and b), GR2 and MR and their sensitivity for cortisol in chapters 3 and 4. The three receptors are expressed in tissues that make up the neuroendocrine stress-axis (brain, hypothalamus and pituitary) and in cells that produce corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). Decreased mRNA expression in brain after prolonged stress suggests an involvement in regulation of hypothalamo-pituitary-interrenal (HPI)-axis activity. In cells of the immune system MR expression is very low compared to GR expression and GR2 is preferentially expressed in lymphocytes. Transactivation assays shows that GR1 is a relatively ‘insensitive’ or ‘stress’ receptor, which can only become activated at stress levels of, whereas GR2 is a ‘sensitive’ receptor that will already be activated at basal levels of cortisol such as occur in non-stressed fish. MR sensitivity for cortisol is intermediate. We predict by tertiary protein modelling and confirmed by transfection assays, that the transactivation capacity of both splice variants (GR1a and GR1b) is similar. Based on the very low expression level in immune cells and the moderate transactivation capacity of MR we concluded that GRs rather then the MR primarily convey stress signals to the immune system. Next, we determined the expression profile of the duplicated GR genes in the immune system in chapters 4 and 5 to investigate the regulation of stress-induced immune modulation. Simultaneously we investigated the expression profile of (among others) heat shock protein 70 (Hsp70). This protein is required for binding of cortisol to the GR, but also has intrinsic immune modulatory functions, as it was shown to downregulate LPS-induced pro-inflammatory cytokine expression in vitro and in vivo. In head kidney phagocytes we found that only physiological stress levels of cortisol could reduce LPS-induced expression of pro-inflammatory cytokines, a response that appears mediated by the ‘stress’ receptor GR1. Moreover, we found that Hsp70 and GR1 (a and b) expression is increased after an immune stimulus in vitro and in vivo, whereas 24 hr restraint stress or 100nM cortisol-treatment hardly increases Hsp70 and GR1 expression levels. This suggests that an immune stimulus rather than increased cortisol levels increases the sensitivity for glucocorticoid regulation and thereby of the cytokine profiles in immune cells.

To find additional genes involved in bidirectional neuroendocrine-immune communication we applied a genome wide screen of 9000 randomly picked cDNA clones. This has the advantage of an unprejudiced overview of regulated genes, but the sensitivity of the technique is limited. In chapter 6 we describe a microarray experiment in which we compared mild acute stress, to prolonged severe immune stimulation. We show that an immune response after parasite infection appears tightly regulated and comparable between individuals, whereas a mild acute stressor allows for more variable gene expression profiles. We found LOC406744 of the DUF727 protein family and nephrosin as new interesting candidate genes that may be involved in neuroendocrine-immune communication.

The key pro-inflammatory cytokine IFN-γ, which is hypothesised to affect neurotransmitter and hormone release, had not been investigated in carp. In chapter 7 we show that carp have duplicate IFN-γ genes that are expressed in immune cells. IFN-γ-2 shows structural and functional characteristics simlar to those in other vertebrate IFN-γ genes and appears to be involved in T-lymphocyte function, whereas IFN-γ-1 is expressed in stimulated B-lymphocytes. Currently recombinant proteins are being produced which will enable us to further elucidate the role of both IFN-γ gene products in the immune system as well as in mediating the neuroendocrine stress response.

Interestingly, as explained in chapter 8, both the glucocorticoid receptor and the IFN-γ genes are duplicated. The duplication-degeneration-complementation (DCC) model has been proposed as an explanation for the high retention of duplicate genes in fishes. The hypothesis assumes that following gene duplication, the two gene copies degenerate over time by random mutation to perform complementary functions that jointly match that of the single ancestral gene, termed ‘subfunctionalisation’. Indeed it appears that the duplicate GR genes have divided the general and ‘stress-related’ functions, reflected by their different sensitivity for cortisol. The duplicate IFN-γ genes appear to have divided B- and T-lymphocyte functions as targets suggested by their gene expression profiles upon selective stimulation.

An important conclusion of this thesis is that duplicated glucocorticoid receptors and heat shock proteins are an integral part of the immune system. Immune stimuli rather than increased cortisol levels control GR and Hsp70 expression in immune cells. The differentially regulated expression of GR genes is at the basis of a balanced pro- and anti-inflammatory
cytokine profile, immune cell viability and thus at the basis of the success of the fishes. This thesis illustrates the importance of extensive and effective bidirectional communication between the neuroendocrine and immune systems, which are at the basis of the successful evolution of the vertebrates.
T-bet expression in the iris and spleen parallels disease expression during endotoxin-induced uveitis
Li, B. ; Yang, P. ; Chu, L. ; Zhou, H. ; Huang, X. ; Zhu, L. ; Kijlstra, A. - \ 2007
Graefes Archive for Clinical and Experimental Ophthalmology 245 (2007)3. - ISSN 0721-832X - p. 407 - 413.
transcription factor - ocular inflammation - lineage commitment - interferon-gamma - dendritic cells - ciliary body - rat - macrophages - injection - cytokines
T lymphocytes have been implicated in the development of endotoxin-induced uveitis (EIU). T-bet is a Th1 cell-specific transcription factor that is involved in differentiation and effector functions. The aim of this study was to investigate kinetics of T-bet expression at the mRNA and protein levels during EIU using real-time PCR and whole-mount immunohistochemistry. Methods A single footpad injection of 200 ¿g of lipopolysaccharide (LPS) was administered to male Wistar rats in order to induce EIU. Clinical changes were followed by slit-lamp examination. The expression of T-bet mRNA in the spleen was evaluated 0, 8, 16, 24, 48, and 96 h after LPS injection using real-time PCR. Immunohistochemistry was performed on the iris whole-mounts as well as on frozen sections of the spleen to evaluate T-bet protein expression. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed on the iris whole-mounts to assay apoptotic cells. Results Uveitis was observed in all rats that received LPS. T-bet+ cells and TUNEL+ cells in the iris whole-mounts showed a similar pattern in cell number and distribution and both types of cells were observed at 8 h, significantly increased 24 h, and decreased 48 h after LPS injection. T-bet expression at both the mRNA and protein levels in spleen also paralleled ocular inflammation. It was weakly detectable after 0 h, increased after 8 h (index 1.3, T-bet+ cells OD 17.43±2.15), reached its peak after 24 h (index 4.00, OD 53.52±4.00), and decreased 48 h following LPS injection (index 1.38, OD 25.75±2.45). Conclusions The results show that T-bet expression in both the iris and the spleen, and in apoptotic cells in the iris parallel the severity of intraocular inflammation after systemic LPS administration. These results suggest that T-bet may play a significant role in the dynamics of EIU.
Real-time gene expression analysis in carp (Cyprinus carpio) skin: inflammatory responses to injury mimicking infection with ectoparasites
Gonzalez, S.F. ; Huising, M.O. ; Stakauska, R. ; Forlenza, M. ; Verburg-van Kemenade, B.M.L. ; Buchmann, K. ; Nielsen, M.E. ; Wiegertjes, G.F. - \ 2007
Developmental and Comparative Immunology 31 (2007)3. - ISSN 0145-305X - p. 244 - 254.
necrosis-factor-alpha - innate immune-responses - rainbow-trout skin - common carp - oncorhynchus-mykiss - molecular-cloning - cxc chemokines - ichthyophthirius-multifiliis - interleukin-1-beta - cytokines
We studied a predictive model of gene expression induced by mechanical injury of fish skin, to resolve the confounding effects on the immune system induced by injury and skin parasite-specific molecules. We applied real time quantitative PCR (RQ-PCR) to measure the expression of the pro-inflammatory cytokines CXCa, CXCb, interleukin (IL)1-beta, tumor necrosis factor alpha (TNFalpha), and the receptors IL1R1, CXCR1 and CXCR2 in skin of Cyprinus carpio after mechanical injury. We also studied the expression of the anti-inflammatory cytokine IL-10. Most obvious, specific up-regulation of the chemokine CXCa, the chemokine receptor CXCR1 and the pro-inflammatory cytokine IL-beta was detected at 2-3h after injury. In order to correlate gene expression patterns after injury with cell migration, we studied chemotaxis of head kidney leukocytes towards lysates of epithelioma papulosum cyprini (EPC) cells. Neutrophilic granulocytes were shown to migrate towards epithelial lysates. Using immunohistochemistry we observed that the early inflammatory response after injury involved an influx of cells, most probably neutrophilic granulocytes, into the injured area. This suggests that the increased expression of pro-inflammatory genes is related to a rapid influx of neutrophilic granulocytes.
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