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Cell and cYTOkine CONcentrations DataBase (CYTOCON DB) is a project undertaken by the InSysBio team and aimed at the development of a database that allows collecting, processing, and visualizing publicly available in vivo human data on baseline concentrations of cells, cytokines, chemokines, and other molecules. Besides manual curation, an important feature of CYTOCON is that most values found in papers are converted from a huge variety of original units (i.e., mg/ml and number of cells per mm2 of biopsy surface section) to unified units: "pM" for cytokine and "kcell/L" for cell concentration. These features of the database can help researchers facilitate the creation and calibration of quantitative systems pharmacology (QSP) models. Possible applications can be: estimation of the average value or variability of the cell, cytokine or chemokine concentrations for patient groups with different characteristics, such as age, gender, disease severity, disease subtype, etc.; and analysis of correlations among the cell, cytokine, or chemokine concentrations in patients with different characteristics, such as severity of the disease. [ABSTRACT FROM AUTHOR]

Aim: To examine pro‐ and anti‐inflammatory cytokines in children with cerebral palsy (CP) at baseline and in response to endotoxin (lipopolysaccharide), and correlate outcomes compared with age‐matched comparisons, to evaluate their ability to mount an immune response. Method: Serum cytokines were assessed in 12 children (eight males, four females; mean age 10y 1mo [SD 1y 8mo], 6–16y) with CP against 12 age‐matched comparisons (eight males, four females; mean age 9y 1mo [SD 1y 1mo]). Pro‐ and anti‐inflammatory cytokines (interleukin‐1β, interleukin‐2, interleukin‐6, interleukin‐8, interleukin‐10, interleukin‐18, tumour necrosis factor [TNF]‐α, TNF‐β, interferon‐γ, granulocyte‐macrophage colony‐stimulating factor [GM‐CSF], vascular endothelial growth factor [VEGF], erythropoietin, and interleukin‐1 receptor antagonist) were measured at baseline and in response to in vitro simulation with lipopolysaccharide by multiplex enzyme‐linked immunosorbent assay. Results: Significantly higher erythropoietin was found at baseline in children with CP compared with the comparison group. There was a strong response to lipopolysaccharide for interleukin‐8, VEGF, TNF‐α, and GM‐CSF in both children with CP and the comparison group; however, there was significant lipopolysaccharide hyporesponsiveness in children with CP compared with the comparison group for interleukin‐1α, interleukin‐1β, interleukin‐2, and interleukin‐6. Interpretation: Altered cytokine responses in children with CP compared with the comparison group demonstrate an altered inflammatory state that may contribute to ongoing sequelae and could be a target for therapy. What this paper adds: Altered inflammatory responses persist in children with cerebral palsy (CP).Erythropoietin is elevated in children with CP compared with the comparison group.Children with CP have reduced interleukin‐1α, interleukin‐1β, interleukin‐2, and interleukin‐6 inflammatory responses to lipopolysaccharide. What this paper adds: Altered inflammatory responses persist in children with cerebral palsy (CP).Erythropoietin is elevated in children with CP compared with the comparison group.Children with CP have reduced interleukin‐1α, interleukin‐1β, interleukin‐2, and interleukin‐6 inflammatory responses to lipopolysaccharide. This article is commented on by Schleiss on pages 365–366 of this issue. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to El Jamaly et al paper. To view this article, visit https://doi.org/10.1111/apt.17155 [ABSTRACT FROM AUTHOR]

Mounting evidence points to increased rates of cardiovascular disease (CVD) among people living with HIV/AIDS (PLWHA). Endothelial dysfunction (loss of endothelium‐dependent vascular relaxation in response to provasodilatory stimuli) constitutes an early pathophysiological event in atherogenesis and CVD. Both HIV‐1 infection and antiretroviral therapy (ART) are implicated in the development of endothelial dysfunction; however, conclusions are frequently drawn from associations shown in epidemiological studies. In this narrative review of mainly in vitro and animal studies, we report on the current understanding of how various HIV‐1 proteins, HIV‐1‐induced proinflammatory cytokines and common antiretroviral drugs directly impact vascular endothelial cells. Proposed cellular mechanisms underlying the switch to a dysfunctional state are discussed, including oxidative stress, impaired expression and regulation of endothelial nitric oxide (NO) synthase (eNOS) and increased expression of vascular adhesion molecules. From the literature, it appears that increased reactive oxygen species (ROS) production, linked to decreased NO bioavailability and ensuing endothelial dysfunction, may be proposed as a putative final common pathway afflicting the vascular endothelium in PLWHA. The HIV‐1‐proteins Tat, Gp120 and Nef in particular, the proinflammatory cytokine, TNF‐α, and the antiretroviral drugs Efavirenz and Lopinavir, most commonly postulated to be primary causal agents of endothelial dysfunction, are also discussed. We conclude that, despite existing evidence from basic research papers, a significant gap remains in terms of the exact underlying cellular mechanisms involved in HIV‐1 and ART induced endothelial dysfunction. Bridging this gap could help pave the way for future strategies to prevent and treat early cardiovascular changes in PLWHA. Endothelial dysfunction is considered an early pathophysiological event in the development of cardiovascular disease, increased rates of which have been observed among people living with HIV/AIDS. HIV‐1 proteins, HIV‐1‐induced proinflammatory cytokines and common antiretroviral drugs have all been linked to endothelial dysfunction, with increased reactive oxygen species production and consequent reduced nitric oxide (NO) bioavailability emerging as the common link. [ABSTRACT FROM AUTHOR]

Abstract: There is increasing evidence that glioblastoma possess ‘stem-like’ cells, low concentrations of which can initiate a tumour. It has been proposed that these cells are radioresistant, and that this property contributes to the poor treatment outcomes of these tumours. In this paper we propose that radioresistance is not simply an intrinsic characteristic of glioma stem cells but a result of interactions between these cells and microenvironmental factors, i.e. the ‘microenvironment – stem cell unit’. The critical role of the microenvironment, along with glioma stem cells, is supported directly or indirectly by the following observations: glioma stem cells have been shown to reside preferentially in specific niches, the characteristics of which are known to influence cellular responses to radiation; radiation modifies environmental factors; and, contrarily to the consistency of clinical data, in vitro experiments have reported a wide variety in the radiation response of these cells. The paper, therefore, focuses on the interaction between tumour stem cells and the microenvironment, analyzing how its various elements (endothelial cells, extracellular matrix, cytokines, nitric oxide, oxygen levels) are affected by radiation and how these might influence the response of tumour stem cells to radiation. Finally, we summarize the ongoing debate on the optimal culture conditions for glioma stem cells and the difficulties in designing assays that reliably characterize their radiation response. [Copyright &y& Elsevier]

The article presents information about abstracts of various papers that will be discussed at the Discussion Group of the 6th European Congress on Epileptology that will be held on June 1, 2004. One of the papers that will be discussed is "Cytokines and Acute Neurodegeneration in CNS Disorders," by S. Allan. Cytokines are a large and varied group of immune molecules that have diverse actions in the brain, including a key role as mediators of acute neurodegeneration. Other papers that will be discussed are "The Role of the Interleukins in Febrile Seizures," by R. Straussberg and "The Significance of Cytokine Production in Clinical Epilepsy," by J. Peltola and K.A. Lehtimaki.

LINKED CONTENT: This article is linked to Takenaka et al papers. To view these articles, visit https://doi.org/10.1111/apt.16551 and https://doi.org/10.1111/apt.16579 [ABSTRACT FROM AUTHOR]

We have established previously that human thyroid epithelial cells (TEC) from patients with autoimmune thyroiditis are able to synthesize cytokines, such as interleukin-1(IL-1) and interleukin-6(IL-6). This paper examines TEC in sections from autoimmune thyroiditis for the in vivo production of tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) using the combined techniques of in situ hybridization and immunohistochemistry. Thyroid tissue from patients with Graves' disease, Hashimoto's disease and non-toxic goitre was examined and both mRNA and the protein of TNF-α were detected in TEC on frozen sections. Representative figures of only Graves' samples are illustrated in this paper. In contrast, using the same methods, IFN-γ was detected only in the infiltrating cells and not in TEC of thyroid tissue from the patients. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1β, by central and peripheral immune cells. Il-1β has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS • Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/pharmacodynamic model for LPS-stimulated ATP-induced Il-1β production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug-receptor interaction. The model has the potential to be used to simulate future trials. AIMS This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODS Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1β production in blood were evaluated. RESULTS Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study ( n= 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSION The model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development. [ABSTRACT FROM AUTHOR]

Introduction: Self-rated health (SRH) is a relevant measure of health as it can predict morbidity, mortality and health-care use. Studies have shown an association between poor SRH and elevated levels of circulating inflammatory cytokines. It is therefore interesting to learn more about the association between asthma, a chronic inflammatory disease with a recognised systemic component and SRH. Objectives: To compare SRH ratings in respondents with and without current asthma. A second aim was to compare SRH with quality-of-life ratings in the same groups. Methods: In 1995, we randomly selected 8200 persons ≥18 years from the population of Stockholm County, Sweden and mailed them a questionnaire. A total of 5355 persons (67.5%) responded. Respondents were divided in two groups, those with and those without current asthma. The groups were further divided by sex and age (18-44 and ≥45 years). SRH was measured with the question 'How do you rate your general health status?' and quality of life with the Gothenburg Quality of Life Instrument and the Ladder of Life. Results: Respondents with asthma rated their health significantly worse than did those without asthma, except women aged 18-44 years. SRH was associated at least as strong as quality of life to asthma with the advantage of being easier to apply (only one item). Conclusion: Information on SRH is easy to obtain and represents an important dimension of health status that potentially can be used as a complement to identify patients who need extra attention to manage their asthma and its consequences. Please cite this paper as: Syk J, Alving K and Undén A-L. Association between self-rated health and asthma: a population-based study. Clin Respir J 2012; 6: 150-158. [ABSTRACT FROM AUTHOR]

Aims: In this paper, we review the literature on the efficacy of anti-inflammatory agents as neuroprotectors in clinical and preclinical stages of schizophrenia. Method: A synthetic and integrative approach was applied to review studies stemming from epidemiology, phenomenology, cognition, genetics and neuroimaging data. We provide conclusions and future directions of research on early-onset schizophrenia. Results: Abnormal inflammatory activation has been demonstrated in schizophrenia. Increases or imbalances in cytokines before birth or during childhood may impact neurodevelopment and produce vulnerability to schizophrenia. The specificity of inflammatory abnormalities in psychiatric disorders is controversial. Similar increases in pro-inflammatory cytokines have been described in other disorders, especially mood and anxiety disorders. One of the most important challenges at this point is the understanding of neurobiological correlates of prodromal stages of schizophrenia. Conclusion: Although future research should investigate the exact role of different cytokines in pathophysiology of schizophrenia, these mediators emerge as promising molecular targets to its prevention and treatment. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Svindland et al. The mucosal and systemic immune responses elicited by a chitosan-adjuvanted intranasal influenza H5N1 vaccine. Influenza and Other Respiratory Viruses DOI:10.1111/j.1750-2659.2011.00271.x. Background Development of influenza vaccines that induce mucosal immunity has been highlighted by the World Health Organisation as a priority (Vaccine 2005;23:1529). Dose-sparing strategies and an efficient mass-vaccination regime will be paramount to reduce the morbidity and mortality of a future H5N1 pandemic. Objectives This study has investigated the immune response and the dose-sparing potential of a chitosan-adjuvanted intranasal H5N1 (RG-14) subunit (SU) vaccine in a mouse model. Methods Groups of mice were intranasally immunised once or twice with a chitosan (5 mg/ml)-adjuvanted SU vaccine [7·5, 15 or 30 μg haemagglutinin (HA)] or with a non-adjuvanted SU vaccine (30 μg HA). For comparison, another group of mice were intranasally immunised with a whole H5N1 (RG-14) virus (WV) vaccine (15 μg HA), and the control group consisted of unimmunised mice. Results The chitosan-adjuvanted SU vaccine induced an immune response superior to that of the non-adjuvanted SU vaccine. Compared with the non-adjuvanted SU group, the chitosan-adjuvanted SU vaccine elicited higher numbers of influenza-specific antibody-secreting cells (ASCs), higher concentrations of local and systemic antibodies and correspondingly an improved haemagglutination inhibition (HI) and single radial haemolysis (SRH) response against both the homologous vaccine strain and drifted H5 strains. We measured a mixed T-helper 1/T-helper 2 cytokine response in the chitosan-adjuvanted SU groups, and these groups had an increased percentage of virus-specific CD4+ T cells producing two Thelper 1 (Th1) cytokines simultaneously compared with the non-adjuvanted SU group. Overall, the WV vaccine induced higher antibody concentrations in sera and an HI and SRH response similar to that of the chitosan-adjuvanted SU vaccine. Furthermore, the WV vaccine formulation showed a stronger bias towards a T-helper 1 profile than the SU vaccine and elicited the highest frequencies of CD4+ Th1 cells simultaneously secreting three different cytokines (INFγ+, IL2+ and INFα+). As expected, two immunisations gave a better immune response than one in all groups. The control group had very low or not detectable results in the performed immunoassays. Conclusion The cross-clade serum reactivity, improved B- and T-cell responses and dose-sparing potential of chitosan show that a chitosan-adjuvanted intranasal influenza vaccine is a promising candidate vaccine for further preclinical development. [ABSTRACT FROM AUTHOR]

Abstract: Progranulin (PGRN) is an autocrine growth factor with multiple functions. This review provides updates about the interplays of PGRN with extracellular matrix proteins, proteolytic enzymes, inflammatory cytokines, and cell surface receptors in cartilage and arthritis, with a special focus on the interaction between PGRN and TNF receptors (TNFR) and its implications in inflammatory arthritis. The paper also highlights Atsttrin, an engineered protein composed of three PGRN fragments that prevents inflammation in several inflammatory arthritis models. Identification of PGRN as a ligand of TNFR and an antagonist of TNFα signaling, together with the discovery of Atsttrin, not only betters our understanding of the pathogenesis of arthritis, but also provides new therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis. [Copyright &y& Elsevier]

Please cite this paper as: Easterbrook et al. (2011) Obese mice have increased morbidity and mortality compared to non-obese mice during infection with the 2009 pandemic H1N1 influenza virus. Influenza and Other Respiratory Viruses 5(6), 418-425. Background Obesity has been identified as an independent risk factor for severe or fatal infection with 2009 pandemic H1N1 influenza (2009 pH1N1), but was not previously recognized for previous pandemic or seasonal influenza infections. Objectives Our aim was to evaluate the role of obesity as an independent risk factor for severity of infection with 2009 pH1N1, seasonal H1N1, or a pathogenic H1N1 influenza virus. Methods Diet-induced obese (DIO) and their non-obese, age-matched control counterparts were inoculated with a 2009 pH1N1, A/California/04/2009 (CA/09), current seasonal H1N1, A/NY/312/2001 (NY312), or highly pathogenic 1918-like H1N1, A/Iowa/Swine/1931 (Sw31), virus. Results Following inoculation with CA/09, DIO mice had higher mortality (80%) than control mice (0%) and lost more weight during infection. No effect of obesity on morbidity and mortality was observed during NY312 or Sw31 infection. Influenza antigen distribution in the alveolar regions of the lungs was more pronounced in DIO than control mice during CA/09 infection at 3 days post-inoculation (dpi), despite similar virus titers. During CA/09 infection, localized interferon-β and proinflammatory cytokine protein responses in the lungs were significantly lower in DIO than control mice. Conversely, serum cytokine concentrations were elevated in DIO, but not control mice following infection with CA/09. The effect of obesity on differential immune responses was abrogated during NY312 or Sw31 infection. Conclusions Together, these data support epidemiologic reports that obesity may be a risk factor for severe 2009 pandemic H1N1 influenza infection, but the role of obesity in seasonal or highly virulent pandemic influenza infection remains unclear. [ABSTRACT FROM AUTHOR]

It is well known that the relationship between child nutrition and infection is bidirectional, i.e. frequent illness can impair nutritional status and poor nutrition can increase the risk of infection. What is less clear is whether infection reduces the effectiveness of nutrition interventions or, vice versa, whether malnutrition lessens the impact of infection control strategies. The objective of this paper is to review the evidence regarding this interaction between nutrition and infection with respect to child growth in low-income populations. Even when there are no obvious symptoms, physiological conditions associated with infections can impair growth by suppressing appetite, impairing absorption of nutrients, increasing nutrient losses and diverting nutrients away from growth. However, there is little direct evidence that nutrition interventions are less effective when infection is common; more research is needed on this question. On the other hand, evidence from four intervention trials suggests that the adverse effects of certain infections (e.g. diarrhoea) on growth can be reduced or eliminated by improving nutrition. Interventions that combine improved nutrition with prevention and control of infections are likely to be most effective for enhancing child growth and development. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Larcombe et al. (2011) Sexual dimorphism in lung function responses to acute influenza A infection. Influenza and Other Respiratory Viruses 5(5), 334-342. Background Males are generally more susceptible to respiratory infections; however, there are few data on the physiological responses to such infections in males and females. Objectives To determine whether sexual dimorphism exists in the physiological/inflammatory responses of weanling and adult BALB/c mice to influenza. Methods Weanling and adult mice of both sexes were inoculated with influenza A or appropriate control solution. Respiratory mechanics, responsiveness to methacholine (MCh), viral titre and bronchoalveolar lavage (BAL) cellular inflammation/cytokines were measured 4 (acute) and 21 (resolution) days post-inoculation. Results Acute infection impaired lung function and induced hyperresponsiveness and cellular inflammation in both sexes at both ages. Males and females responded differently with female mice developing greater abnormalities in tissue damping and elastance and greater MCh responsiveness at both ages. BAL inflammation, cytokines and lung viral titres were similar between the sexes. At resolution, all parameters had returned to baseline levels in adults and weanling males; however, female weanlings had persisting hyperresponsiveness. Conclusions We identified significant differences in the physiological responses of male and female mice to infection with influenza A, which occurred in the absence of variation in viral titre and cellular inflammation. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Wong et al. (2011) Oseltamivir treatment of mice before or after mild influenza infection reduced cellular and cytokine inflammation in the lung. Influenza and Other Respiratory Viruses 5(5), 343-350. Background Lung inflammation is a critical determinant of influenza infection outcomes but is seldom evaluated in animal studies of oseltamivir (OS), which have focused on viral titre and survival. Objectives To study the effects of pre- and post-infection dosing with OS on viral replication and inflammation in a mouse model of non-lethal influenza infection. Methods BALB/c mice were infected with a laboratory-adapted H3N1 strain of influenza. In pre-dosing studies, OS was gavaged twice daily (1 and 10 mg/kg/day) from 4 hours prior to infection and continuing for 5 days (d) post-infection (p.i). In the second post-infection dosing study, dosing at 10 mg/kg/day began at 24-48 hours p.i. Mice were dissected at d3, d5 and d7 p.i. (pre-dosing study) and d5 p.i. (post-dosing study). Lung viral titres were determined by plaque assay. Bronchoalveolar lavage fluid (BALF) was collected and used for the quantitation of inflammatory cells and mediators. Results Pre-infection dosing of OS reduced total cells, neutrophils and macrophages in BALF. With pre- or post-infection dosing, the pro-inflammatory mediators TNF-α, IL-1β, IL-6 and granulocyte-macrophage colony-stimulating factor, the neutrophil chemokines keratinocyte-derived chemokine and MIP-1α and the macrophage chemokine MCP-1 were reduced in BALF. Pre-dosing with 1 mg/kg OS did not reduce viral titres, while 10 mg/kg slightly reduced viral titres at d3 and d5 p.i. Conclusions Oseltamivir reduced the inflammatory response to influenza when given pre- or post-infection. This anti-inflammatory effect may contribute to the clinical benefit of OS. [ABSTRACT FROM AUTHOR]

Patients with sarcoidosis exhibit exercise intolerance-related fatigue and increased levels of circulating proinflammatory cytokines at rest. Exercise may result in increased plasma cytokine levels (PCLs) in healthy adults, but such a relationship has not been studied in sarcoidosis patients. To assess relationship of fatigue in sarcoidosis with PCLs at rest and with cardiopulmonary exercise testing (CPET). We assessed lung function, CPET data, multidimensional fatigue inventory, plasma tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations before, immediately after, and 4-6 h following CPET in 22 sarcoidosis patients (13 receiving immunomodulatory drugs) and 22 controls. Patients exhibited greater fatigue, reduced cardiorespiratory function, higher Medical Research Council (MRC) scores and higher plasma TNF-α concentrations than controls at all times. Plasma IL-1β levels did not differ between cohorts. Patients exhibited a 28% increase (statistically not significant) in TNF-α level immediately post exercise. Plasma IL-β concentrations did not change among cohorts. Treated patients exhibited higher MRC and physical fatigue scores and lower breathing reserve, but no differences in cardiorespiratory function or PCLs compared to untreated patients. In treated patients, pre-exercise plasma IL-1β correlated with physical fatigue, reduced motivation and total fatigue; TNF-α levels only correlated with general fatigue score. Treated sarcoidosis patients exhibit a relation between physical fatigue, reduced motivation and total fatigue and pre-exercise plasma IL-1β concentrations. Acute exercise does not increase PCLs. Whether the reduced MRC score and physical fatigue in treated patients is related to the therapy or to the underlying inflammatory process is difficult to determine. Please cite this paper as: Baydur A, Alavy B, Nawathe A, Liu S, Louie S and Sharma OP. Fatigue and plasma cytokine concentrations at rest and during exercise in patients with sarcoidosis. Clin Respir J 2011; 5: 156-164. [ABSTRACT FROM AUTHOR]

Peripheral blood CD4 CD45RO T cells activated in vitro are able to induce expression of tumour necrosis factor-α (TNF-α) in monocytes via a contact-dependent mechanism. Activation is achieved either with interleukin-2 (IL-2)/IL-6/TNF-α over an 8-day period or cross-linking CD3 using anti-CD3 antibody for 48 hr. In this paper, we show that the p38 mitogen-activated protein kinase (MAPK) signalling pathway played different roles in the generation of effector function in these two types of activated T cells. In anti-CD3 activated T cells, p38 MAPK is a negative regulator for anti-CD3 induced cell proliferation and has no significant effect on the acquisition of either the effector function (induction of monocyte-derived TNF-α) or production of T-cell cytokines. In contrast, the p38 MAPK signalling pathway is required for the acquisition of cytokine-induced effector function and promotes cell proliferation and cytokine production. [ABSTRACT FROM AUTHOR]

Caco-2 cells form an enterocyte-like monolayer that has been used to explore small intestinal microparticle uptake. They are a useful functional model for the investigation of in vivo drug delivery systems and the uptake of particulate environmental pollutants. The aim of this paper was to determine if the previously reported decrease in Caco-2 transepithelial resistance following exposure to macrophages was matched by increased microparticle uptake, especially as macrophage phagocytosis simulates removal of particles from the subepithelial compartment. Caco-2 cells were grown as a monoculture for 21 days on insert membranes. A compartmentalised model involved Caco-2 cells in the upper compartment, with THP-1-derived macrophages adhering to the base of the underlying well, the two cell populations communicating only through the shared culture medium. Caco-2 cells were also cultured in macrophage-conditioned medium and all groups were exposed apically to 2 μm latex particles for 5 or 60 min. Parameters measured were: transepithelial resistance; cytokine levels; cell dimensions and the distribution of nuclei, actin and junctional proteins. Subepithelial particle numbers, defined as those located below the insert membrane, were also counted and were significantly increased in the Caco-2/macrophage model, with over 90% associated with the macrophages. Other changes induced by the presence of macrophages included decreased transepithelial resistance levels, diffuse localisation of some junctional proteins, higher proinflammatory cytokine levels, disorganisation of cell shape and decreased cell height associated with actin reorganisation. Macrophage-conditioned medium produced a smaller transepithelial resistance decrease than the Caco-2/macrophage model and there were few other changes. In conclusion, culture of Caco-2 cells with underlying macrophages produced a lower, less organised epithelium and greater microparticle uptake. [ABSTRACT FROM AUTHOR]

The transcription factor IRF-3 is activated by microbial invasions and produces a variety of cytokines including type-I interferon. Upon microbial infection, IRF-3 is phosphorylated at its C-terminal regulatory domain, then oligomerized, translocated into the nucleus, and here it binds to CBP/p300. Although a number of studies have been reported investigating the activation mechanism of IRF-3, there are a number of unresolved issues, especially on the phosphorylation sites, the oligomerization process and the binding mechanism with CBP/p300. In this report, the phosphorylated IRF-3 regulatory domain (IRF-3 RD) was prepared using the kinase IKK-i, and the active form of phosphorylated IRF-3 RD was identified. The paper also reports the crystal structure of the active form of the phosphorylated IRF-3 RD. Furthermore, the phosphorylation of Ser386 was found to be essential for its dimerization and binding with CBP/p300 using mutational analysis and mass spectrometry. Thus, we conclude that the phosphorylation of Ser386 is essential for activation of IRF-3. [ABSTRACT FROM AUTHOR]

The ultimate outcome of T cell receptor recognition is determined by the context in which the antigen is encountered. In this fashion both antigen-presenting cells and T cells must integrate multiple environmental cues in the form of pathogen-associated molecular patterns, cytokines and accessory molecule signals. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental signals critical to regulating metabolism and cell survival. In this paper we review the data demonstrating that mTOR integrates signals from the immune microenvironment and therefore facilitates the generation of the adaptive immune response. Specifically, we review the role of mTOR in promoting dendritic cell activation and maturation, in regulating full T cell activation versus anergy, and influencing the induction of regulatory T cells. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Takenaka et al and Rakowsky et al papers. To view these articles, visit https://doi.org/10.1111/apt.16551 and https://doi.org/10.1111/apt.16571 [ABSTRACT FROM AUTHOR]

The article presents a review of papers published in "Arthritis & Rheumatism" (A&R) from July 1995 through June 2000, focusing on the documentation of the advances in anticytokine therapeutics for rheumatic diseases. It is said that the evolution of knowledge about the role of cytokines in inflammation and tissue damage in rheumatic diseases led to the application of the principles of rational drug design to the development of therapeutic approaches for the diseases.

In the last decade, preclinical studies have provided a better characterization of the homeostatic and maladaptive mechanisms occurring either during the process of epileptogenesis or after the permanent epileptic state has emerged. Experimental evidence supported by clinical observations highlighted the possibility that brain inflammation is a common factor contributing, or predisposing, to the occurrence of seizures and cell death, in various forms of epilepsy of different etiologies. Expression of proinflammatory cytokines, as a hallmark of brain inflammation, has been demonstrated in glia in various experimental models of seizures and in human epilepsies. Experimental studies in rodents with perturbed cytokine systems indicate that these inflammatory mediators can alter neuronal excitability and affect cell survival by activating transcriptional and posttranslational intracellular pathways. This paper will provide an overview on the current knowledge in this field to discuss mechanistic hypotheses into the study of pathogenesis of epilepsy and recognize new potential therapeutic options. [ABSTRACT FROM AUTHOR]

Introduction: Inflammation is an important constituent of the pathology of chronic obstructive pulmonary disease (COPD), leading to alveolar destruction and airway remodelling. Objective: The aim of this study was to assess the difference in plasma biomarkers of inflammation between asymptomatic smokers and patients with COPD. Methods: We used commercially available enzyme-linked immunosorbent assay kits to measure the plasma levels of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), monocyte chemotactic protein-1 (MCP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and tissue inhibitor of metalloproteinase-2 (TIMP-2) on two occasions with a 2-week interval in patients with COPD ( n = 20), asymptomatic smokers ( n = 10) and healthy lifelong non-smokers ( n = 10). The participants were characterised clinically, physiologically and by quantitative computed tomography by measuring the relative area of emphysema below −910 Hounsfield units (RA-910). Results: The results of the biomarker measurements on the two occasions were highly reproducible. Patients with COPD had significantly higher plasma levels of IL-8 ( P = 0.004) and significantly lower levels of TIMP-1 ( P = 0.02) than smokers and non-smokers. There was no statistically significant difference between the three groups in the level of TNF-α, MMP-9, MCP-1 and TIMP-2. The IL-8/TIMP-1 ratio correlated significantly with the degree of airway obstruction measured as forced expiratory volume in 1 second (FEV1) % predicted ( r = −0.47, P < 0.01); with the diffusion capacity ( r = −0.41, P < 0.01); and with the grade of emphysema measured as RA-910 ( r = 0.39, P = 0.01). Conclusion: These findings suggest that the measurement of plasma biomarkers, such as IL-8/TIMP-1, may aid to discriminate patients with COPD from smokers at lower risk of developing COPD. Please cite this paper as: Shaker SB, von Wachenfeldt KA, Larsson S, Mile I, Persdotter S, Dahlbäck M, Broberg P, Stoel B, Bach KS, Hestad M, Fehniger TE and Dirksen A. Identification of patients with chronic obstructive pulmonary disease (COPD) by measurement of plasma biomarkers. The Clinical Respiratory Journal 2008; 2: 17–25. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to summarize some of the newly recognized in utero factors that interact with gene expression to establish the structural and physiologic processes that will serve the individual long term. These may be common to all mammals and probably reflect evolutionary plasticity, which improves species survival. The concepts of programming, fetal-maternal microchimerism, growth factors, and transgenerational nutritional affects are explored. [ABSTRACT FROM AUTHOR]

Interleukin 18 (IL-18) has been identified as a potent upstream cytokine required for upregulation of IFN-γ secretion that plays a crucial role in polarization of Th1 type of immune response. Considering the potential applications of the cytokine in immunomodulation, it has been characterized in many livestock species including cattle, equines, canines, felines and porcines. In this paper we report the isolation, cloning sequencing and expression of caprine precursor IL-18. Full-length caprine IL-18 cDNA was isolated from mitogen-stimulated adherent peripheral blood mononuclear cells using reverse transcription polymerase chain reaction (RT-PCR). The cDNA contained an open reading frame of 579 bp encoding a putative polypeptide of 192 amino acids. Deduced amino acid sequence of caprine IL-18 showed varying amino acid identity with the published sequences of other domestic ruminant species ranging from 94.3% to 96.9%, while it shared over 78% aa identity with other domestic animals. Pairwise multiple aligned sequences showed a deletion of Glu31in caprine IL-18 unlike in other species. Recombinant caprine IL-18 was produced in Escherichia coli, which cross-reacted with two antiporcine IL-18 monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Innate and adaptive immune functions decline with age, leading to increased susceptibility to infectious diseases and cancer, and reduced responses to preventive vaccination in the elderly population. Macrophages function as ‘pathogen sensors’ and play an important role in the initiation of inflammatory responses, elimination of pathogens, manipulation of the adaptive immune response and reparation of damaged tissue. In this paper, we review the literature addressing the impact of aging on the macrophage population. [ABSTRACT FROM AUTHOR]

Ceramide has been recognized as a common intracellular second messenger for various cytokines, growth factors and other stimuli, such as CD95, chemotherapeutic drugs and stress factors. To understand the role of ceramide during apoptosis and other cellular responses, it is critically important to characterize direct targets of ceramide action. In this paper, we show that ceramide specifically binds to and activates the endosomal acidic aspartate protease cathepsin D. Direct interaction of ceramide with cathepsin D results in autocatalytic proteolysis of the 52 kDa pre-pro cathepsin D to form the enzymatically active 48/32 kDa isoforms of cathepsin D. Add sphingomyelinase (A-SMase)-deficient cells show decreased cathepsin D activity, which could be reconstituted by transfection with A-SMase cDNA. The results of our study identify cathepsin D as the first endosomal ceramide target that colocalizes with and may mediate downstream signaling effects of A-SMase. [ABSTRACT FROM AUTHOR]

It is now well documented that the mode of primary stimulation in the mouse determines the ratio of Th1-, Th0- or Th2-type T cells obtained. In this paper we determine whether driving and cloning human peripheral blood mononuclear cells (PBMC) non-specifically with interleukin-2 (IL-2) and/ or IL-4 and mitogen, will differentially select T cells for IL-10 production. The presence of IL-2 during culture (with or without IL-4) yielded predominantly Th1-type clones (81% of clones with IL-2 alone and 77% with IL-2 + IL-4) and a low frequency of Th0-type clones (19% of clones with IL-2 and 10% of clones with IL-2 + IL-4), whereas IL-4 alone increased the yield of the IL-4 producing Th0 (35%) clones. The proportions of IL-2-producing clones did not alter with treatment; however, the combination of IL-2 + IL-4 altered the proportions of IL-10-producing clones. 47% of IL-2-cultured cells and 51% of IL-4-cultured cells produced IL-10 respectively, whereas only 22% of clones driven with IL-2 + IL-4 produced detectable levels of IL-10. Thus in the preliminary experiments described here we have demonstrated that the cytokines used to initially drive out human T cells and maintain the T-cell growth can skew the Th1/Th2/Th0 cytokine profiles of the clones obtained from mitogen-stimulated cultures. Moreover and unexpectedly the proportion of IL-10-producing cells is altered. These results are important in interpreting analysis of the cytokine profiles of human T cells and raise questions concerning how we should derive T-cell clones for a cytokine analysis that truly reflects the in vivo situation. [ABSTRACT FROM AUTHOR]

CD27 is a T-cell surface antigen expressed on the majority of peripheral T cells and belongs to a newly defined receptor family including the iow-affinity nerve growth factor receptor, tumour necrosis factor (TNF) receptors, the B-cell activation antigen CD40, and the Fas antigen. Although the function of CD27 has not been defined, several experimental observations support the notion that this molecule plays an important role in the process of T-cell activation. In this paper, we have demonstrated that a rapid hyperphosphorylation of CD27 is induced by a cyclic AMP-inducing agent, forskolin, and a membrane-permeable cAMP analogue, 8-bromo-cAMP, as well as phorbol 12-myristate 13-acetate (PMA). In addition, increased phosphorylation of CD27 in T-cell activation either via CD2 or CD3 pathways was strongly suppressed by a cyclic nucleotide-dependent kinase inhibitor, H-8, but only slightly by a protein kinase C inhibitor, staurosporine. These results suggest that protein kinase A might be a key kinase responsible for CD27 phosphorytation in the process of T-cell activation. CD27 is the first T-cell surface antigen demonstrated to be phosphorylated by the cyclic AMP-protein kinase A-mediated pathway. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Verstockt et al papers. To view these articles, visit https://doi.org/10.1111/apt.15126, and https://doi.org/10.1111/apt.15212. [ABSTRACT FROM AUTHOR]

Reports of Chagas disease are increasing in non-endemic populations across the globe. Apart from vector eradication and prevention efforts by public health organizations, current pharmacological interventions are sparse and show important side effects. In this issue of the BJP, Andrade et al. elegantly demonstrate a new pharmacological paradigm whereby Trypanosoma cruzi host cell invasion requires significant cross-talk between receptors for kinins and endothelins. It is shown, for example, that acting via both ETA and ETB receptors, endothelin-1 (ET-1) cooperates with the (TLR2/CXCR2/B2 kinin receptor) complex to activate inflammatory processes in response to invading trypomastigotes. This study by Andrade et al. prompts, however, several important questions, summarized in this Commentary, such as the putative role of chymase-dependent production of ET-1, the contentious protective role of ACE inhibitors in Chagasic patients, the unexplored role of de novo formed B1 receptors for kinins triggered by cytokines and the putative role of compartmentalized calcium pools in host cell invasion by trypomastigotes. LINKED ARTICLE This article is a commentary on Andrade et al., pp. 1333-1347 of this issue. To view this paper visit [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Cremon et al paper. To view this article visit https://doi.org/10.1111/apt.13958. [ABSTRACT FROM AUTHOR]

The article discusses papers presented in a symposium entitled "Neuroimmune Interactions" at the Experimental Biology meeting held in Washington, D.C. on May 1, 2007. An overview of how immune-neuroendocrine systems cross-communicate was presented by Eduardo Arzt of Buenos Aires, Argentina. The importance of hormones and neuropeptides as immunomodulators in the thymus and lymph nodes was demonstrated by Wilson Savino of Rio de Janeiro, Brazil. The role of cytokines in neuroimmunomodulation in inflammation was investigated by Julio Licinio.

An abstract of the conference paper "Correlation between second trimester 3D-placental volumetry and vascularization, cytokines in the amniotic fluid and fetal weight at birth," by B. Meurer and colleagues is presented.

A conference paper is presented that aims to determine whether the production of tumor necrosis factor (TNF)-α from monocytes due to Escherichia coli O157:H7 supernatant and purified verotoxins (VTs) could be modulated by the p38 kinase inhibitor SB203580. The study found that both E. coli O157 supernatant and VTs can upregulate the production of inflammatory cytokines such as TNF-α from monocytes and create a pro-inflammatory signal.

A conference paper is presented about the effect of bacterial stimulation on the production of interleukin (IL)-10 and transforming growth factor (TGF)-β and the effect of these cytokines, along with prostaglandin E2 (PGE2), on tumor necrosis factor-α levels in the human blood. The study found that the PGE2 is the most effective than IL-10 and TGF-β and it can endogenously control the level of IL-10. Furthermore, it showed that their interactions overlap with each other.

A conference paper about the levels of serum cytokine in male with proven coronary artery disease is presented. It aims to measure the serum cytokine levels in a cohort of 78 men with coronary artery disease. In doing so, the researchers had taken blood samples from the patients who undergone coronary angiography and who had a diagnosis of coronary artery disease. Results supported the connection of interleukin-1β in the development of coronary disease.