Background: Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by chronic inflammation of the gastrointestinal tract, with overlapping clinical characteristics and unknown etiology. ...We reasoned that in intestinal inflammation the initial activation of the innate immune response fails to resolve, finally resulting in uncontrolled chronic inflammatory bowel disease.
Methods: To identify the early inflammatory events in colitis that remain active in human chronic colitis, we analyzed the changes of the colonic transcriptome during acute experimental colitis and compared the outcome with previously published profiles of affected tissues from patients with UC and CD, and as a control for intestinal inflammation in general, tissues from celiac disease patients. Rheumatoid arthritis synovial tissues were included as a nonintestinal inflammatory disease. The expression profiles of each disease were analyzed separately, in which diseased tissues were compared to unaffected tissues from the same anatomical location.
Results: Gene ontology analysis of significantly regulated genes revealed a marked activation of immunity and defense processes in all diseases, except celiac disease, where immune activation is less prominent. The control region of upregulated genes contained an increase in Ets2 binding sites in experimental colitis, UC, and rheumatoid arthritis, and were associated with upregulated immune activity. In contrast, upregulated genes in celiac disease harbored the transcription factor binding site GLI, which binds to the Gli family of transcription factors involved in hedgehog signaling, affecting development and morphogenesis.
Conclusion: Ets2 may be an important transcription factor driving inflammation in acute as well as chronic inflammatory disease.
(Inflamm Bowel Dis 2008)
OBJECTIVE: Dysregulation of tumour necrosis factor alpha (TNF alpha) production is thought to be important in rheumatoid arthritis. Since pentoxifylline and thalidomide inhibit endotoxin induced TNF ...production in vitro, these drugs were tested in an open study in rheumatoid arthritis patients to assess toxicity, the effect on TNF production, and the antiarthritic effects. METHODS: 12 patients with active rheumatoid arthritis were treated with 1200 mg pentoxifylline and 100 mg thalidomide a day during 12 weeks. In addition, TNF production was assessed by ex vivo whole blood cultures stimulated with endotoxin. RESULTS: Adverse events such as xerostomia, drowsiness, and constipation occurred in almost all patients, which led to discontinuation in three. The drugs halved the TNF production capacity during treatment (ANOVA, P < 0.03) whereas production capacity of interleukin (IL) 6, IL-10, and IL-12 was not affected. Of the nine patients who completed the study, five fulfilled the ACR-20% response criteria after 12 weeks of treatment. CONCLUSIONS: Although pentoxifylline/thalidomide reduced the production capacity of TNF, the benefit/side effects ratio was poor due to multiple adverse effects, while clinical observation suggests limited efficacy.
Abstract Crohn’s disease (CD) is characterized by an aberrant immune response to bacterial products stimulating TLR, in genetically susceptible hosts. Next to mutations in the TLR signaling molecule ...NOD2, several other immune response- and autophagy-genes contribute to CD. Since only 10–20% of cases can be explained by a NOD2 defect, we searched for additional TLR-related disease-causing factors. We analyzed the LPS response of peripheral blood mononuclear cells from 23 CD patients in remission, compared to 16 controls in a time course experiment. Individuals with any of the three major contributing NOD2 mutations were excluded. Overall, the LPS-responsive gene transcript levels, determined by low density arrays, were significantly lower in CD patients. In particular IL-1A expression was severely reduced in CD patients (ninefold reduction, p = 0.001). Quantification of several important TLR4 signal transducers and cytokines identified MAP3K4 as a candidate signaling molecule with reduced expression in CD patients, which might explain the low IL-1A expression. Silencing of MAP3K4 by lentiviral shRNA transduction indeed showed that the expression of IL-1A was specifically dependent on this kinase. Furthermore, the expression of GSK3β, an inhibitor of MAP3K4, was increased in CD patients. In conclusion, we identified a novel TLR signaling defect in CD patients involving MAP3K4 and IL-1A. This confirms the hypothesis that CD patients, despite their massive intestinal inflammation, suffer from a relative immune deficiency in TLR-mediated cytokine production.
Abstract Acute myocardial infarction (AMI) is accompanied by increased expression of Toll like receptors (TLR)-2 and TLR4 on circulating monocytes. In animal models, blocking TLR2/4 signaling reduces ...inflammatory cell influx and infarct size. The clinical consequences of TLR activation during AMI in humans are unknown, including its role in long-term cardiac functional outcome Therefore, we analyzed gene expression in whole blood samples from 28 patients with an acute ST elevation myocardial infarction (STEMI), enrolled in the EXenatide trial for AMI patients (EXAMI), both at admission and after 4-month follow-up, by whole genome expression profiling and real-time PCR. Cardiac function was determined by cardiac magnetic resonance (CMR) imaging at baseline and after 4-month follow-up. TLR pathway activation was shown by increased expression of TLR4 and its downstream genes, including IL-18R1, IL-18R2, IL-8, MMP9, HIF1A, and NFKBIA. In contrast, expression of the classical TLR-induced gene s , TNF, was reduced. Bioinformatics analysis and in vitro experiments explained this noncanonical TLR response by identification of a pivotal role for HIF-1α. The extent of TLR activation and IL-18R1/2 expression in circulating cells preceded massive troponin-T release and correlated with the CMR-measured ischemic area (R = 0.48, p = 0.01). In conclusion, we identified a novel HIF-1-dependent noncanonical TLR activation pathway in circulating leukocytes leading to enhanced IL-18R expression which correlated with the magnitude of the ischemic area. This knowledge may contribute to our mechanistic understanding of the involvement of the innate immune system during STEMI and may yield diagnostic and prognostic value for patients with myocardial infarction.
Objective
To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive ...biomarkers.
Methods
The study group comprised 109 anti–citrullinated protein antibody (ACPA)– and/or rheumatoid factor–positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction.
Results
In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at‐risk patients, based on differential expression of immune‐related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN)–mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval 95% CI 2.8–156.1 P = 0.003) for the subgroup characterized by increased expression of genes involved in IFN‐mediated immunity and/or cytokine/chemokine‐activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21–0.70 P = 0.002). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease.
Conclusion
The results of this study indicate that IFN‐mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine.
We examined if serum concentrations Interferon gamma-induced protein (IP-10) is a potential clinical biomarker for cancer-related-fatigue (CRF). Fatigue scores and IP-10 concentrations were measured ...from curatively treated fatigued cancer patients randomized to either cognitive behavioral therapy (CBT, n = 26) or waiting-list (WL, n = 13). No correlation was found between baseline IP-10 level and fatigue severity and no significant differences in IP-10 serum levels were observed between fatigued and matched non-fatigued patients (n = 22). Relative changes in IP-10 concentrations from baseline to six-month follow-up were not significantly different between the CBT and WL conditions. In this study, IP-10 showed low potential as clinical CRF biomarker.
Trial registration: This study is registered at
ClinicalTrials.gov
(NCT01096641).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The role of interleukin-12 (IL-12) in Th1 cell differentiation is well established. The heterodimer p70, composed of a p40 and a p35 chain, is the biologically active form. IL-12 production by human ...monocytes is enhanced by interferon-gamma (IFN-gamma) and inhibited by IL-10 and prostaglandin E2 (PGE2). Peripheral blood mononuclear cells from human immunodeficiency virus (HIV)-infected individuals reportedly have impaired IL-12 p40 and p70 production on stimulation with Staphylococcus aureus Cowan I (SAC) in vitro. Both PGE2 and IL-10 previously were proposed to be instrumental in this defect in IL-12 production. Here, we studied IL-12 p40 and p70 production in relation to IL-10 and PGE2 production in whole blood cultures from HIV-infected individuals. On stimulation with lipopolysaccharide, IL-12 production was normal. However, on stimulation with SAC, IL-12 p40 and p70 production was decreased in HIV-infected individuals and correlated significantly with decreased peripheral blood CD4+ T-cell number and T-cell reactivity to CD3 monoclonal antibody in vitro. However, IL-10 and PGE2 production in cultures from HIV-infected individuals was normal and did not relate to IL-12 production. In conclusion, IL-12 production by cells from HIV-infected individuals is impaired under certain conditions in vitro and this decrease is independent of IL-10 or PGE2 production.
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