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Acute Phase Response (acute + phase_response)
Selected AbstractsThe birth process initiates an acute phase reaction in the fetus-newborn infantACTA PAEDIATRICA, Issue 9 2000G Marchini Our goal was to investigate whether the normal birth process stimulated an acute phase response in healthy infants with physiological changes in the circulating levels of acute phase cytokines and acute phase proteins. We also monitored body temperature, body weight and behavioural state in order to investigate if clinical signs of acute phase reaction were present. We made cross-sectional measurements of interleukin-1,, interleukin-6, C-reactive protein, serum amyloid A, procalcitonin, prealbumin, body weight, body temperature and the duration of the sleeping period during the first four postnatal days. We found an increase in interleukin-6 (p < 0.001) during the first day, followed by an increase in C-reactive protein, serum amyloid A and procalcitonin on the second postnatal day (p < 0.01). The level of prealbumin fell after birth and reached its lowest value at 3 d of age (p < 0,001). Interleukin-l p remained unchanged. The duration of the sleeping period was longer during the first day (p < 0.01). There was an increase in body temperature during the first day (p < 0.01). Maximal weight loss was during the first 2 d. Conclusions: The normal birth process and extra-uterine adaptation stimulates an acute phase reaction in the newborn infant with a release of interleukin-6 and acute phase proteins and a depression of prealbumin. This reaction, as the body's first line inflammatory defence system, probably affects the infant's behaviour, nutritional state as well as the regulation of body temperature. [source] Systemic concentrations of antioxidants and biomarkers of macromolecular oxidative damage in horses with grass sicknessEQUINE VETERINARY JOURNAL, Issue 2 2003B. C. McGORUM Summary Reasons for performing study: The aetiopathogenesis of equine grass sickness (EGS) is unknown. The role of free radical-mediated neuronal damage has not previously been investigated in this condition. Objectives: To investigate the potential contribution of oxidative damage and antioxidant status to neurodegeneration in EGS. Methods: Systemic levels of surrogate biomarkers were determined in 10 horses with acute EGS and in 2 control populations; 10 healthy horses co-grazing with the 10 EGS horses at the onset of clinical disease, and 10 healthy mares grazing where EGS has not been reported. Results: EGS horses had alterations in levels of several antioxidants, consistent with oxidative stress, the acute phase response and/or the secondary metabolic complications of EGS. EGS horses had elevated plasma dihydroxyphenylalanine (DOPA) levels. Conclusions: The elevated DOPA levels probably reflected a generalised disturbance of catecholamine metabolism rather than increased DOPA production via free radical-mediated oxidation of tyrosine. However, there was no evidence of systemic macromolecular oxidative damage. Potential clinical relevance: Further work is required to determine whether macromolecular oxidative damage occurring at the neuronal level contributes to EGS. [source] T-cell-specific deletion of gp130 renders the highly susceptible IL-10-deficient mouse resistant to intestinal nematode infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2009Nicolas Fasnacht Abstract Gp130 is the common receptor of the IL-6 family of cytokines and is involved in many biological processes, including acute phase response, inflammation and immune reactions. To investigate the role of gp130 under inflammatory conditions, T-cell-specific conditional gp130 mice were first bred to the IL-10-deficient background and were then infected with the gastrointestinal nematode Trichuris muris. While IL-10,/, mice were highly susceptible to T. muris, developed a mixed Th1/Th17 response and displayed severe inflammation of the caecum, infection of mice with an additional T-cell-specific deletion of gp130 signalling completely reversed the phenotype. These mice showed an accelerated worm expulsion that was associated with the rapid generation of a strong Th2 immune response and a significant increase in Foxp3-expressing Treg. Therefore, gp130 signalling in T cells regulates a switch between proinflammatory and pathogenic Th1/Th17 cells and regulatory Th2/Treg in vivo. Taken together, the data demonstrate that gp130 signalling in T cells is a positive regulator of inflammatory processes, favouring the Th1/Th17 axis. [source] Hepatocyte nuclear factor-4, interacts with other hepatocyte nuclear factors in regulating transthyretin gene expressionFEBS JOURNAL, Issue 19 2010Zhongyan Wang Transthyretin is a negative acute phase protein whose serum level decreases during the acute phase response. Transthyretin gene expression in the liver is regulated at the transcriptional level, and is controlled by hepatocyte nuclear factor (HNF)-4, and other HNFs. The site-directed mutagenesis of HNF-4, HNF-1, HNF-3 and HNF-6 binding sites in the transthyretin proximal promoter dramatically decreases transthyretin promoter activity. Interestingly, the mutation of the HNF-4 binding site not only abolishes the response to HNF-4,, but also reduces significantly the response to other HNFs. However, mutation of the HNF-4 binding site merely affects the specific binding of HNF-4,, but not other HNFs, suggesting that an intact HNF-4 binding site not only provides a platform for specific interaction with HNF-4,, but also facilitates the interaction of HNF-4, with other HNFs. In a cytokine-induced acute phase response cell culture model, we observed a significant reduction in the binding of HNF-4,, HNF-1,, HNF-3, and HNF-6, to the transthyretin promoter, which correlates with a decrease in transthyretin expression after injury. These findings provide new insights into the mechanism of the negative transcriptional regulation of the transthyretin gene after injury caused by a decrease in the binding of HNFs and a modulation in their coordinated interactions. [source] Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl,CoA dehydrogenase (MCAD),deficient mice,HEPATOLOGY, Issue 6 2008Hilde Herrema Medium-chain acyl,coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD,/, mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD,/, mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1, (Pgc-1,) and decreased peroxisome proliferator-activated receptor alpha (Ppar ,) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD,/, mice in both conditions, suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD,/, mice. During the APR, however, this flux was significantly decreased (,20%) in MCAD,/, mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD,/, mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD,/, mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD,/, mice, was mainly due to enhanced peripheral glucose uptake. Conclusion: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation. (HEPATOLOGY 2008.) [source] Serum amyloid A has antiviral activity against hepatitis C virus by inhibiting virus entry in a cell culture system,HEPATOLOGY, Issue 6 2006Muriel Lavie Serum amyloid A (SAA) is an acute phase protein produced by the liver. SAA concentration increases markedly in the serum following inflammation and infection. Large increases in SAA concentration during the acute phase response suggest that SAA has a beneficial role in host defense. This study sought to determine the effect of SAA on hepatitis C virus (HCV) infectivity using retroviral particles pseudotyped with HCV envelope glycoproteins (HCVpp) and the recently developed cell culture system for HCV (HCVcc). SAA inhibited HCVpp and HCVcc infection in a dose-dependent manner by affecting an early step of the virus life cycle. Further characterization with HCVpp indicated that SAA blocks virus entry by interacting with the viral particle. In addition, the antiviral activity of SAA was strongly reduced when high-density lipoproteins (HDL) were coincubated with SAA. However, HDL had only a slight effect on the antiviral activity of SAA when HCVpp was first preincubated with SAA. Furthermore, analyses of SAA in sera of chronic HCV patients revealed the presence of variable levels of SAA with abnormally elevated concentrations in some cases. However, no obvious clinical correlation was found between SAA levels and HCV viral loads. In conclusion, our data demonstrate an antiviral activity for SAA and suggest a tight relationship between SAA and HDL in modulating HCV infectivity. (HEPATOLOGY 2006;44:1626,1634.) [source] Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis,INFLAMMATORY BOWEL DISEASES, Issue 5 2010Brad A. Pasternak MD Abstract Background: Systemic exposure to lipopolysaccharide (LPS) has been linked to clinical disease activity in adults with inflammatory bowel disease (IBD). We hypothesized that markers of LPS exposure and the acute phase response (APR) would be increased in pediatric IBD patients with growth failure, and that LPS signaling would be required for induction of the APR in murine colitis. Methods: Serum markers of LPS exposure, endotoxin core IgA antibody (EndoCAb), and the APR, LPS binding protein (LBP) were quantified in pediatric IBD patients and controls. LBP and cytokine production were determined after administration of trinitrobenzene sulfonic acid (TNBS) enemas to mice with genetic deletion of Toll-Like receptor 4 (TLR4), and wildtype (WT) controls. Results: Serum EndoCAb and LBP were significantly elevated in patients with Crohn's disease (CD), compared to disease controls with ulcerative colitis (UC) and healthy controls (P < 0.001). This was independent of disease activity or location. CD patients with elevated serum EndoCAb and LBP exhibited linear growth failure which persisted during therapy. Serum LBP increased in WT mice following TNBS administration, in conjunction with increased serum TNF-,, IL-6, and IL-10, and expansion of regulatory T-cell numbers. Both the APR and expansion of foxp3+ T cells were abrogated in TLR4-deficient mice, in conjunction with a reduction in acute weight loss. Conclusions: LPS exposure and a persistent APR are associated with growth failure in pediatric CD. LPS signaling is required for the APR in murine colitis. Therapies targeting this pathway may benefit the subset of patients with refractory growth failure. (Inflamm Bowel Dis 2010) [source] Increased strength of erythrocyte aggregates in blood of patients with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2009Nitsan Maharshak MD Abstract Background: Increased strength of red blood cell (RBC) aggregates are present during the acute inflammatory response and contribute to erythrocyte aggregation and may lead to microvascular dysfunction. Inflammatory bowel diseases (IBDs) are characterized by damage to the bowel wall. This damage may be at least partially attributed to microvascular ischemia caused by enhanced erythrocyte aggregation. The aim of this study was to evaluate the strength of RBC aggregates in the blood of patients with IBD. Methods: The strengths of RBC aggregates were characterized by integrative RBC aggregation parameters, determined by measuring of RBC aggregation as a function of shear stress. The results are represented as the area under the curve (AUC) of aggregate size plotted against shear stress. For each patient, dynamic aggregation and disaggregation of RBC were recorded and analyzed according to the RBC aggregate size distribution at the different shear stresses. Aggregation indices were correlated with disease activity and inflammatory biomarkers. Results: We examined 53 IBD patients and 63 controls. IBD patients had significantly elevated concentrations of inflammation-sensitive proteins and aggregation parameters. The strength of large aggregates, represented by AUC for large fraction aggregates, among patients (15.2 ± 18.6) was double that of controls (7 ± 10.9) (P = 0.006). The strength of large aggregates correlated with disease activity (r = 0.340; P < 0.001) with concentration of fibrinogen (r = 0.575; P < 0.001) and with concentration of high sensitivity C-reactive protein (r = 0.386; P < 0.001). Conclusions: The strength of RBC aggregates is increased in patients with IBD and correlates with the intensity of the acute phase response. This could contribute to bowel damage in these diseases. (Inflamm Bowel Dis 2009) [source] The erythrocyte adhesiveness/aggregation test for the detection of an acute phase response and for the assessment of its intensityINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 4 2002N. Maharshak Summary We have developed a simple slide test and image analysis to reveal the state of erythrocyte adhesiveness/aggregation in the peripheral blood of patients with various degrees of the humoral acute phase response. The significant correlation between the results of the erythrocyte adhesiveness/aggregation test (EAAT), the erythrocyte sedimentation rate and fibrinogen concentration support the notion that it is possible to use the EAAT as a marker for the intensity of the acute phase response. Within a group of 860 individuals, we were able to differentiate effectively between groups of patients with a different intensity of humoral acute phase response. The present study confirms previous observations that support the applicability of the EAAT to routine clinical practice. [source] Alpha2 macroglobulin elevation without an acute phase response in depressed adults with Down's syndrome: implications,JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 6 2000J. A. Tsiouris Abstract Studies of immune function during depression in persons without intellectual disability (ID) have revealed elevated levels of ,2 macroglobulin (,2M) and an acute phase protein (APP) response. Clinical observation suggests that people with Down's syndrome (DS) may have associated genetic abnormalities in their immune systems. The APP response and ,2M changes in depressed versus non-depressed adults with DS was the subject of the present study. The serum pan-proteinase inhibitor ,2M, and the AP proteins c-reactive protein (CRP), ,1 antitrypsin (,1AT), ceruloplasmin (Cp), ,2 Macroglobulin (,2M), transthyretin (Trans), serum amyloid protein (SAP), and albumin (Alb) were measured in 38 adults with DS, 19 of whom were diagnosed with and 19 without depression using a sandwich enzyme-linked immunosorbent assay (ELISA). The DSM-IV criteria were used for diagnoses. Medical and neurological examinations excluded medical disorders associated with APP response. Only ,2M and CRP were significantly different in the depressed versus non-depressed groups. The ,2M was higher, a response similar to one observed in depressed people without ID, but the CRP was lower in the depressed group, especially in those subjects not on psychotropic medications, contrary to the expected APP response to depression. The results suggest that ,2M elevation in depressed adults with DS is independent of the APP response. An alternative explanation for its elevation is proposed linking the core symptom of depression with the mammalian dormancy/hibernation process. Further studies are needed to confirm that ,2M elevation is specific to depression and that it might provide a helpful marker for the diagnosis of depression in people with ID. [source] C-reactive protein and coronary heart disease: a critical reviewJOURNAL OF INTERNAL MEDICINE, Issue 4 2008J. P. Casas Abstract. Modestly elevated baseline concentrations of C-reactive protein (CRP), the classical acute phase protein, are associated with the long-term risk of coronary heart disease in general populations, whilst the major acute phase response of CRP following myocardial infarction is associated with death and cardiac complications. The pathogenic and clinical significance of these associations is controversial. Here we critically review the evidence and describe large-scale epidemiological studies, novel experiments and possible specific therapies which will rigorously inform the debate. We distinguish between the potential pathogenicity of high acute phase circulating CRP concentrations in individuals with substantial tissue damage and modest but persistent increases in baseline values in generally healthy subjects. [source] Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase responseJOURNAL OF INTERNAL MEDICINE, Issue 3 2004A. Simon Abstract. Background., Classical type hyper-immunoglobulin D (IgD) syndrome (HIDS) is an hereditary auto-inflammatory disorder, characterized by recurrent episodes of fever, lymphadenopathy, abdominal distress and a high serum concentration of IgD. It is caused by mevalonate kinase deficiency. Objective., To further characterize the acute phase response during fever attacks in HIDS in order to improve diagnosis. Subjects., Twenty-two mevalonate kinase-deficient HIDS patients. Methods., Blood samples were drawn during and in between febrile attacks, and concentrations ofC-reactive protein (CRP), ferritin, procalcitonin, pentraxin 3, IgD and cholesterol in several lipoprotein fractions were determined. Results., The marked acute phase response at the time of a fever attack in classical type HIDS is reflected by a rise in CRP accompanied by a moderate but statistically significant rise in procalcitonin and pentraxin 3. In only two of 22 patients, procalcitonin concentration rose above 2 ng mL,1 during fever attack, compatible with the noninfectious nature of these attacks. Ferritin does not reach the high concentrations found in adult-onset Still's disease. Despite the defect in mevalonate kinase, a component of cholesterol metabolism, serum cholesterol did not change during attacks. IgD concentration is elevated regardless of disease activity, although there is appreciable variation during life. Its role in HIDS remains unclear. Conclusion., The combination of high CRP concentration plus procalcitonin concentration <2 ng mL,1 in a symptomatic HIDS patient might indicate a febrile attack without (bacterial) infection; this observation warrants further investigation for its usefulness as a marker in clinical practice. [source] Periodontal therapy: a novel non-drug-induced experimental model to study human inflammationJOURNAL OF PERIODONTAL RESEARCH, Issue 5 2004F. D'Aiuto Background:, Chronic periodontitis causes a low-grade systemic inflammatory response; its standard treatment, however, induces an acute inflammatory response. The aim of this study was to describe the systemic inflammatory reactions to an intensive periodontal treatment regimen. Methods:, Fourteen otherwise healthy subjects suffering from severe chronic periodontitis were enrolled in a 1 month pilot single-blind trial. Intensive periodontal treatment, consisting of full-mouth subgingival root debridement delivered within a 6-h period, was performed. Periodontal parameters were recorded before and 1 month after completion of treatment. Blood samples were taken at baseline and 1, 3, 5, 7 and 30 days after treatment. Interleukin-1 receptor antagonist (IL-1Ra), Interleukin-6 (IL-6) and C-reactive protein (CRP) serum concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Complete blood counts were also performed. Results:, One day after treatment, mild neutrophilia and monocytosis (p < 0.05) and lymphopenia (p < 0.01) were accompanied by a sharp increase in inflammatory markers (IL-1Ra, IL-6, p < 0.01). A 10-fold increase in CRP (p < 0.001) was detected on day 1 and its kinetics followed a pattern of a classical acute phase response (significantly raised concentrations up to 1 week, p < 0.01). At 3,7 days after treatment, subjects presented also with a mild tendency towards a normocytic anaemic state (p < 0.01) and a degree of lympho-thrombocytosis (p < 0.05). The observed changes were similar to those expected following the well-characterized endotoxin-challenge model of inflammation. Conclusions:, Intensive periodontal treatment produced an acute systemic inflammatory response of 1 week duration and might represent an alternative to classic endotoxin-challenge or drug-induced models to study acute inflammation in humans. [source] 2-D DIGE and MS/MS analysis of protein serum expression in rats housed in concrete and clay cages in winterPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 17 2008Jong-Choon Kim Abstract In a previous study, we examined the physiological responses of male Sprague,Dawley rats over a 4-week exposure to concrete and clay cages. No general toxicological changes were observed in rats exposed to either of the two cage types in summer. Under winter conditions, however, various general toxicological effects were detected in rats housed in concrete cages, although rats housed in clay cages showed no such effects. The infrared thermographic examination indicated that skin temperature in the concrete-housed rats was abnormally low, but not so in the clay-housed rats. We examined proteomic changes in the serum of rats housed in winter in concrete and clay cages using two-dimensional differential in-gel electrophoresis and mass spectrometry/mass spectrometry. Five proteins were identified and quantitatively validated; all were cold stress-induced, acute phase proteins that were either up-regulated (haptoglobin) or down-regulated (alpha-1-inhibitor III, alpha-2u globulin, complement component 3, and vitamin D-binding protein) in the concrete-housed rats. These results suggest that the 4-week exposure to a concrete cage in winter elicited a typical systemic inflammatory reaction (i.e. acute phase response) in the exposed rats. [source] Proteomic changes in rat serum, polymorphonuclear and mononuclear leukocytes after chronic nicotine administrationPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2005Chiara Piubelli Abstract In order to gain information about the effect triggered at the molecular level by nicotine, its neuroimmunomodulatory properties and its impact on the pathogenesis of inflammatory diseases, peripheral blood serum and leukocytes of rat submitted to passive nicotine administration were subjected to proteomic investigation. Serum, polymorphonuclear (PMN) and mononuclear (MN) leukocytes from chronically treated animals and from control animals were analysed by a two-dimensional (2-D) gel electrophoresis/mass spectrometry approach to detect differentially expressed proteins. The nicotine regimen selected is known to have a stimulatory effect on locomotor activity and to produce a sensitisation of the mesolimbic dopamine system mechanism involved in addiction development. After 2-D gel analysis and matching, 36,spots in serum, seven in PMN and five in MN were found to display a statistical difference in their expression and were subjected to matrix-assisted laser desorption/ionization-time of flight-mass spectrometry peptide fingerprinting for protein identification. Fifteen different proteins were identified. The results indicate an overall impact of nicotine on proteins involved in a variety of cellular and metabolic pathways, including acute phase response (suggesting the effect on inflammatory cascades and more in general on the immune system), oxidative stress metabolism and assembly and regulation of cytoskeleton. In particular, the observed changes imply a general reduction in the inflammatory response with a concomitant increased unbalance of the oxidative stress metabolism in the periphery and point to a number of potential noninvasive markers for the central nervous system (CNS) and non-CNS mediated activities of nicotine. [source] Changes in the natural abundance of 13CO2/12CO2 in breath due to lipopolysacchride-induced acute phase responseRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 23 2009Daniel E. Butz The natural abundance of carbon-13 in blood proteins increases during the cachectic state and may be a biomarker for disease status. We hypothesized a corresponding drop in the relative abundance of 13C in breath CO2. Using the lipopolysacchride (LPS)-induced endotoxemia model of the acute cachectic state, we demonstrated that the acute phase response causes shifts in the stable isotopes of carbon in exhaled CO2 (13CO2/12CO2 delta value) shortly after administration of LPS while glucocorticoid treatment does not. Mice were injected with LPS and stable isotopes of blood amino acids and carbon in exhaled CO2 were monitored. An increase in the relative isotopic mass of serum alanine, proline and threonine was observed at 3,h after LPS injection. Breath delta values began dropping immediately after administration of LPS, and were 4,5 delta values lower than those of the control animals by 2.5,h after injection. A corresponding drop in delta value was not observed with dexamethasone treatment. Thus protein synthesis during the acute phase response probably caused the fractionation of stable isotopes observed in the plasma amino acids and in exhaled breath 13CO2 delta values. The exhaled breath 13CO2 delta value may be a valuable real-time biomarker of cachexia associated with an acute phase response due to endotoxemia. Copyright © 2009 John Wiley & Sons, Ltd. [source] Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1,: a proteomic analysisBIOTECHNOLOGY & BIOENGINEERING, Issue 4 2005Arul Jayaraman Abstract The liver is the major source of proteins used throughout the body for various functions. Upon injury or infection, an acute phase response (APR) is initiated in the liver that is primarily mediated by inflammatory cytokines such as interleukin-1, (IL-1,) and interleukin-6. Among others, the APR is characterized by an altered protein synthetic profile. We used two-dimensional gel electrophoresis to study the dynamics of changes in protein synthesis in hepatocytes exposed to these inflammatory cytokines. Protein profiles were quantified using image analysis and further analyzed using multivariate statistical methods. Our results indicate that IL-1, and IL-6 each induces secreted protein responses with distinct dynamics and dose-dependence. Parallel stimulation by IL-1, and IL-6 results in a protein pattern indistinguishable from the IL-1, pattern, indicating a dominant effect of IL-1, over IL-6 at the doses tested. Multidimensional scaling (MDS) of correlation distances between protein secretion levels revealed two protein pairs that are robustly co-secreted across the various cytokine stimulation conditions, suggesting shared regulatory pathways. Finally, we also used multivariate alternating conditional expectation (MACE) to identify transformation functions that discriminated the cytokine-stimulated and untreated hepatocyte-secreted protein profiles. Our analysis indicates that the expression of neutrophil gelatinase-associated lipocalin (NGAL) was sufficient to discriminate between IL-1, and IL-6 stimulation. The combination of proteomics and multivariate analysis is expected to provide new information on the cellular regulatory networks involved in generating specific cellular responses. © 2005 Wiley Periodicals, Inc. [source] An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver diseaseCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009A. Lemmers Summary In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130,Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130,Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease. [source] | |||||||||||||