Multisystemic production of interleukin 10 limits the severity of acute pancreatitis in mice.
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ABSTRACT:
SUBMITTER: Van Laethem JL
PROVIDER: S-EPMC1727255 | biostudies-other | 1998 Sep
REPOSITORIES: biostudies-other
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Project description:The association between interleukin-10 (IL-10) gene rs1800896 polymorphism and susceptibility to acute pancreatitis (AP) has been investigated in several studies, but with contradictory findings. Therefore, a comprehensive meta-analysis is needed to assess the strength of such association.Literatures on PubMed, EMBASE, and CNKI were searched to identify relevant studies. The strength of association between IL-10 gene rs1800896 polymorphism and AP risk was assessed using pooled odds ratios and 95% confidence intervals.Totally 7 case-control studies involving 1527 cases and 1511 controls were identified. Analyses proved that IL-10 gene rs1800896 polymorphism was significantly associated with an increased risk of AP. Stratification analysis of ethnicity found such significant association only among Asians, but not Caucasians.IL-10 gene rs1800896 polymorphism increases the risk of AP.
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Project description:Interleukin (IL)-6, IL-8, IL-10, and C-reactive protein (CRP) have been evaluated for predicting outcomes of acute pancreatitis. However, there is considerable variation in their performance among different studies. We evaluate their accuracy in predicting progression to severe pancreatitis.Serum IL-6, IL-8, IL-10, and CRP levels were measured within 24 h of admission in forty patients of clinically predicted severe acute pancreatitis (SAP). Persistent organ failure (>48 h) defined SAP. The performance of inflammatory markers was evaluated in predicting the progression of pancreatitis.IL-6 ≥28.90 pg/mL had a sensitivity of 62.86%, specificity of 80%, positive predictive value (PPV) of 95.65%, LR+ of 3.1429, LR- of 0.4643, and diagnostic odds ratio (DOR) of 6.7692; IL-8 ≥88.70 pg/mL had a sensitivity of 60%, specificity of 80%, PPV of 95.45%, LR+ of 3.000, LR- of 0.5000, and DOR of 6.000; IL-10 ≤5.70 pg/mL had DOR of 0.2647, sensitivity of 51.43%, specificity of 20%, PPV of 81.82%, LR+ of 0.6429, and LR- of 2.4286. CRP ≥110.00 mg/L had DOR of 2.3636, sensitivity of 37.14%, specificity of 80%, PPV of 92.86%, LR+ of 1.8571, and LR of 0.7857.IL-6 ≥28.90 pg/mL, measured within 48 h of onset is the best among the tested biomarkers in this study for predicting the progression to severe pancreatitis.
| S-EPMC5538089 | biostudies-other
Project description:Interferon-induced transmembrane (IFITM) proteins are a family of viral restriction factors that inhibit the entry processes of several pathogenic viruses, including influenza A virus (IAV), in vitro. Here we report that IAV-infected knockout mice lacking the Ifitm locus on chromosome 7 exhibited accelerated disease progression, greater mortality, and higher pulmonary and systemic viral burdens as compared to wild type controls. We further observed that the phenotype of Ifitm3-specific knockout mice was indistinguishable from that of mice lacking the entire Ifitm locus. Ifitm3 was expressed by IAV target cells including alveolar type II pneumocytes and tracheal/bronchial respiratory epithelial cells. Robust Ifitm3 expression was also observed in several tissues in the absence of infection. Among murine Ifitm promoters, only that of Ifitm3 could be induced by type I and II interferons. Ifitm3 could also be upregulated by the gp130 cytokines IL-6 and oncostatin M on cells expressing appropriate receptors, suggesting that multiple cytokine signals could contribute to Ifitm3 expression in a cell or tissue-specific manner. Collectively, these findings establish a central role for Ifitm3 in limiting acute influenza in vivo, and provide further insight into Ifitm3 expression and regulation.
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Project description:High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis.We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1(flox/flox) mice). Acute pancreatitis was induced in these mice (HMGB1(flox/flox) mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses.After injection of l-arginine or cerulein, Pdx1-Cre; HMGB1(flox/flox) mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1(flox/flox) mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor ?B, degradation of inhibitor of ?B, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor ?B in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1(flox/flox) and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection.In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage.
| S-EPMC3965592 | biostudies-literature
Project description:BackgroundVagus nerve stimulation (VNS) is effective in reducing inflammation in various diseases, such as rheumatoid arthritis, colitis and acute kidney injury. The anti-inflammatory effect of vagus nerve in these diseases necessitates the interactions of neural activation and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. In this study, we aimed to investigate the effect of VNS on severity in experimental acute pancreatitis (AP).MethodsTwo independent AP models were used, which induced in ICR mice with caerulein or pancreatic duct ligation (PDL). Thirty minutes after modeling, the left cervical carotid sheath containing the vagus nerve was electrically stimulated for 2 min. Plasma lipase and amylase activities, TNF-α levels and pancreas histologic damage were evaluated. In caerulein mice, the percentages of α7nAChR+ macrophage in pancreas and spleen were assessed by flow cytometry. Furthermore, splenectomy and adoptive transfer of VNS-conditioned α7nAChR splenocytes were performed in caerulein mice to evaluate the role of spleen in the protective effect of VNS.ResultsVNS reduced plasma lipase and amylase activities, blunted the concentrations of TNF-α and protected against pancreas histologic damage in two AP models. Survival rates were improved in the PDL model after VNS. In caerulein AP mice, VNS increased the percentages of α7nAChR+ macrophages in pancreas and spleen. Adoptive transfer of VNS-treated α7nAChR splenocytes provided protection against pancreatitis in recipient mice. However, splenectomy did not abolish the protective effect of VNS.ConclusionsVNS reduces disease severity and attenuates inflammation in AP mice. This effect is independent of spleen and is probably related to α7nAChR on macrophage.
| S-EPMC7840568 | biostudies-literature
Project description:Overactivation of the innate immune response underlies many forms of liver injury including that caused by hepatotoxins. Recent studies have demonstrated that macrophage autophagy regulates innate immunity and resultant tissue inflammation. Although hepatocyte autophagy has been shown to modulate hepatic injury, little is known about the role of autophagy in hepatic macrophages during the inflammatory response to acute toxic liver injury. Our aim therefore was to determine whether macrophage autophagy functions to down regulate hepatic inflammation.Mice with a LysM-CRE-mediated macrophage knockout of the autophagy gene ATG5 were examined for their response to toxin-induced liver injury from D-galactosamine/lipopolysaccharide (GalN/LPS).Knockout mice had increased liver injury from GalN/LPS as determined by significant increases in serum alanine aminotransferase, histological evidence of liver injury, positive terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, caspase activation and mortality as compared to littermate controls. Levels of proinflammatory tumor necrosis factor and interleukin (IL)-6 hepatic mRNA and serum protein were unchanged, but serum IL-1? was significantly increased in knockout mice. The increase in serum IL-1? was secondary to elevated hepatic caspase 1 activation and inflammasome-mediated cleavage of pro-IL-1? to its active form. Cultured hepatic macrophages from GalN/LPS-treated knockout mice had similarly increased IL-1? production. Dysregulation of IL-1? was the mechanism of increased liver injury as an IL-1 receptor antagonist prevented injury in knockout mice in concert with decreased neutrophil activation.Macrophage autophagy functions to limit acute toxin-induced liver injury and death by inhibiting the generation of inflammasome-dependent IL-1?.
| S-EPMC4691423 | biostudies-literature
Project description:The type of immune response during development of acute pancreatitis (AP) determines disease severity. Pancreatic epithelial cells express the interleukin (IL)-22 receptor A1 (IL-22RA1). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates expression of IL-22. We investigated sources and role of IL-22 in the pancreas, along with the effects of AhR activation on IL-22 expression and AP progression in mice.We analyzed the effects of recombinant IL-22, a monoclonal antibody against IL-22, and agonists and antagonists of AhR in mice with AP (induced with caerulein or a choline-deficient diet supplemented with DL-ethionine) and control mice. We also analyzed transgenic mice with AhR deficiency (AhR(d) and AhR(-/-) mice).CD4(+) T cells were the main source of IL-22 in pancreatic tissues from healthy mice. During development of AP, numbers of IL-22(+) CD4(+) T cells were reduced, whereas IL-22RA1 was up-regulated. Consistent with high levels of IL-22RA1 expression, pancreatic acinar cells responded to IL-22 signaling via signal transducers and activators of transcription 3; administration of IL-22 reduced AP and associated lung injury in mice. AhR was required for production of IL-22 and protected mice from AP. Mice that did not respond to AhR activation developed AP, but administration of IL-22 reduced AP; blockade of IL-22 reversed the ability of activated AhR to protect against AP.AhR activation protects mice from AP by inducing expression of IL-22. AhR therefore mediates interactions between pancreatic leukocytes and epithelial cells and might be developed as a therapeutic target.
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Project description:Background:The effect of diet on risk of acute pancreatitis (AP) has been suggested by prior studies, but the association of dietary habits with severity of AP has not been previously evaluated. Objective:The objective of the study was to assess differences in reported dietary habits in patients with severe AP compared with those with mild or moderate AP. Methods:A prospectively maintained cohort of patients with AP was utilized. A brief questionnaire on dietary habits was implemented. Dietary habits were categorized based on the overall type of diet, fruit/vegetable servings, fat content, dairy consumption, dessert/sweets consumption, and fluid intake. Patients were grouped into mild/moderate and severe AP. Multivariate analysis was used to determine whether dietary habits have an independent association with AP severity. Results:407 patients with AP were studied. Mean patient age was 51 y, and 202 (50%) were men. 29% of patients were smokers and 46% actively consumed alcohol. 225 patients had mild AP, 103 moderate AP, and 79 developed severe AP. The 3 groups were comparable in race, body mass index, etiology of AP, and comorbidities. Dietary factors were overall comparable between the groups except for diet type: subjects with severe AP had a higher percentage of consuming a meat-rich diet (84%) than patients with mild AP (72%) and moderate AP (67%) (P = 0.04). Based on multivariable logistic regression, the OR of developing severe AP was 2.5 (95% CI: 1.24-5.32, P = 0.01) between patients who eat a meat-rich diet and those who consume a vegetable-based diet. Conclusions:A meat-rich diet is independently associated with the development of persistent organ failure (severe disease) in patients with AP. These findings require further evaluation and could be useful for patient counseling, risk stratification, and disease prevention. This study is registered at clinicaltrials.gov as NCT03075605.
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Project description:Cannabis is the most commonly and widely used illicit drug in the world and is also the most commonly used drug of abuse in alcohol drinkers. Experimental studies have shown conflicting results of the effects of cannabis on the severity of acute pancreatitis (AP). The purpose of this study is to ascertain the clinical effects of simultaneous alcohol and cannabis use on severity at presentation and outcomes of acute alcoholic pancreatitis (AAP).A retrospective review was conducted on the patients discharged with principle or secondary diagnosis of AP using ICD-9 & ICD-10 codes during the time period from January 2006 to December 2015 at a large community-based hospital in Central Georgia. Patients with alcoholic pancreatitis with cannabis (CB+) and without cannabis (CB-) use were identified and were matched with sex and age.Our study findings showed that a greater percentage of CB+ patients did not have a systemic inflammatory response syndrome (SIRS) score (P=0.043), had a lower BISAP score (P=0.031), and had a significantly lower BUN level (P=0.033), but there was no difference in the Balthazar Index and revised Atlanta classification severity between the two groups. CB+ patients tended to need less ICU care than CB- patients (P=0.059).Based on our findings, we found that CB+ patients had less severe presentation of AAP indicating that cannabis could modulate the inflammatory effect of alcohol on the pancreas. Further large scale prospective studies are needed to confirm our results.
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Project description:Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several proinflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. Interleukin (IL)-27 is a recently discovered member of the IL-6/IL-12 family. The IL-27 receptor is composed of IL-27 receptor A (WSX-1) and gp130 and is required for all established IL-27 signaling pathways. The expression of the IL-27 subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown.The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development.Atherosclerosis-prone Ldlr(-/-) mice transplanted with Il27ra(-/-) bone marrow and fed Western diet for 16 weeks developed significantly larger atherosclerotic lesions in aortic roots, aortic arches, and abdominal aortas. Augmented disease correlated with increased accumulation of CD45(+) leukocytes and CD4(+) T cells in the aorta, which produced increased amounts of IL-17A and tumor necrosis factor. Several chemokines, including CCL2, were upregulated in the aortas of Ldlr(-/-) mice receiving Il27ra(-/-) bone marrow, resulting in accumulation of CD11b(+) and CD11c(+) macrophages and dendritic cells in atherosclerotic aortas.The absence of anti-inflammatory IL-27 signaling skews immune responses toward T-helper 17, resulting in increased production of IL-17A and tumor necrosis factor, which in turn enhances chemokine expression and drives the accumulation of proatherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel antiatherogenic role for IL-27 receptor signaling, which acts to suppress the production of proinflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas.
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