Browsing by Subject "IL-6"

Now showing 1 - 6 of 6
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    Diagnostic and Prognostic Plasma Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation
    (Elsevier, 2018-04) Seo, Sachiko; Yu, Jeffrey; Jenkins, Isaac C.; Leisenring, Wendy M.; Steven-Ayers, Terry; Kuypers, Jane M.; Huang, Meei-Li; Jerome, Keith R.; Boeckh, Michael; Paczesny, Sophie; Pediatrics, School of Medicine
    Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication after hematopoietic cell transplantation (HCT) and is difficult to diagnose. In 41 patients with IPS, we evaluated 6 candidate proteins in plasma samples at day 7 post-HCT and at onset of IPS to identify potential diagnostic or prognostic biomarkers for IPS. Samples at similar times from 162 HCT recipients without documented infections and 37 HCT recipients with respiratory viral pneumonia served as controls. In multivariable models, a combination of Stimulation-2 (ST2; odds ratio [OR], 2.8; P < .001) and IL-6 (OR, 1.4; P = .025) was the best panel for distinguishing IPS at diagnosis from unaffected controls, whereas tumor necrosis factor receptor 1 (TNFR1; OR, 2.9; P = .002) was the best marker when comparing patients with IPS and viral pneumonia. The areas under the curve of the receiver operating characteristic (ROC) curves for discriminating between IPS and unaffected controls at day 7 post-HCT were .8 for ST2, .75 for IL-6, and .68 for TNFR1. Using estimated sensitivity and specificity values from cutoffs determined with the ROC analysis (cutoff level: ST2, 21 ng/mL; IL-6, 61 pg/mL; TNFR1, 3421 pg/mL), we calculated positive predictive values (PPV) for a range of estimated population prevalence values of IPS. Among the 3 markers, ST2 showed the highest PPV for IPS occurrence. Based on an assumed prevalence of 8%, a positive ST2 test increased likelihood of IPS to 50%. We conclude that a prospective validation study is warranted to determine whether a plasma biomarker panel can aid the noninvasive diagnosis and prognosis of IPS.
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    IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase associated lipocalin during acute kidney injury
    (Elsevier, 2020-05) Skrypnyk, Nataliya I.; Gist, Katja M.; Okamura, Kayo; Montford, John R.; You, Zhiying; Yang, Haichun; Moldovan, Radu; Bodoni, Evelyn; Blaine, Judith T.; Edelstein, Charles L.; Soranno, Danielle E.; Kirkbride-Romeo, Lara A.; Griffin, Benjamin R.; Altmann, Chris; Faubel, Sarah; Pediatrics, School of Medicine
    Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.
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    Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone
    (Wiley, 2014-06) Teramachi, Jumpei; Zhou, Hua; Subler, Mark A.; Kitagawa, Yukiko; Galson, Deborah L.; Dempster, David W.; Windle, Jolene J.; Kurihara, Noriyoshi; Roodman, G. David; Department of Medicine, IU School of Medicine
    Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6(-/-) mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ), nor produce elevated levels of IL-6. We previously generated p62(P394L) knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2 D3 . Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (µQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice contributes to increased responsivity to 1,25-(OH)2 D3 and increased OCL numbers, but is not sufficient to induce Paget's-like OCLs or bone lesions in vivo.
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    SOCS3 is a novel bi-functional regulator of muscle growth and wasting
    (Office of the Vice Chancellor for Research, 2015-04-17) Bonetto, Andrea; Camperi, Andrea; Aydogdu, Tufan; Pons, Marianne; Au, Ernie D.; Koniaris, Leonidas G.; Zimmers, Teresa A.
    Disease states such as cancer and other inflammatory conditions often show elevated IL-6 levels that correlate with muscle wasting and mortality. Previously we reported that STAT3, a transcription factor downstream of IL-6 binding to its receptor, plays a causative role in cancer cachexia, and that STAT3 inhibition prevents muscle wasting. Others have also shown that STAT3 blockade rescues cachexia in a murine model of kidney failure. Altogether these results established STAT3 as a regulator of muscle mass. One of STAT3 downstream target genes is the Suppressor of cytokine signaling-3 (SOCS-3). Interestingly, SOCS3 has been reported to inhibit the IL-6/STAT3 signaling by means of a feedback mechanism. In particular, SOCS3 can prevent further STAT3 activation by inhibiting the activation of JAK kinases, competing for receptor binding motifs and targeting the receptor for proteasomal degradation. We thus sought to determine the role of SOCS3 in muscle growth regulation and whether SOCS3 can improve muscle wasting in conditions of high IL-6. Adenoviral-mediated SOCS3 overexpression in C2C12 myotubes caused hypertrophy and rescued IL-6-induced myofiber shrinkage. Similarly, SOCS3 gene transfer in the tibialis muscle of tumor hosts and burn-injured mice prevented muscle atrophy due to elevated IL-6. We then generated MLC-SOCS3 transgenic mice overexpressing SOCS3 from a muscle-specific promoter. Interestingly, these animals exhibit a complex sexually dimorphic phenotype. Indeed, female mice showed higher SOCS3 protein levels in skeletal muscle compared to the males, consistently with decreased pSTAT3 expression. Despite reduced or unchanged body weights, the MLC-SOCS3 transgenics generally showed larger skeletal muscles compared to their wild-type littermates. 1-weekold and adult MLC-SOCS3 mice were also characterized by significantly larger muscle cross-sectional area. However, only adult male mice showed reduced number of muscle fibers and increased number of central nuclei, thus suggesting that SOCS3 could affect myogenesis and differentiation. On this line and consistent with previous reports, primary myoblasts isolated from MLC-SOCS3 mice were shown to proliferate at a lower rate and formed hypertrophic fibers upon differentiation. Furthermore, MLC-SOCS3 myotubes as well as C2C12 expressing SOCS3 were refractory to both catabolic (IL-6) and anabolic (IGF-1 and GH) stimuli. These data suggest that SOCS3 could act as a bi-functional regulator of muscle growth, possibly by affecting differentiation and limiting both IL-6/STAT3- induced wasting as well as IGF-1/GH-associated signaling. Further investigation is needed to define whether SOCS3 may play a role in the activation of muscle satellite cells and to support the use of SOCS3 as a therapeutic approach in cachexia and sarcopenia.
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    Tumor, Fat and Skeletal Muscle Crosstalk via IL-6R Trans-Signaling Mediates Pancreatic Cancer Cachexia
    (2020-10) Rupert, Joseph Emil; Zimmers, Teresa A.; Broxmeyer, Hal E.; Goebl, Mark G.; O'Connell, Thomas M.; Quilliam, Lawrence A.
    Cachexia, the involuntary loss of fat and muscle is associated with pancreatic ductal adenocarcinoma (PDAC), contributing to its 90% 5-year mortality rate. Elevated Interleukin-6 (IL-6) expression is associated with cachexia severity and reduced survival in patients. IL-6 in cancer is well documented, but IL-6 signaling crosstalk among tissues is not. IL-6 signals by binding membrane-bound IL-6 receptor (IL-6R) (classical signaling) or soluble IL- 6R (sIL6R; trans-signaling) produced by shedding of the membrane receptor primarily from muscle, liver and leukocytes. Herein I investigate the role of tumorderived IL-6 on muscle and fat crosstalk in PDAC. Loss of IL-6 expression in murine KPC PDAC cells was accomplished by CRISPR/Cas9 mutagenesis of the Il6 gene. Orthotopic KPC IL-6 knockout (KPC-IL-6KO) tumor-bearing mice had reduced cachexia, with attenuated fat loss and no significant muscle loss, and longer survival versus KPC controls. Only KPC tumor-bearing mice had significant myosteatosis, aberrant branched chain amino acid and fatty acid metabolism, and reduced pyruvate entry into the TCA-cycle, determined by increased pyruvate dehydrogenase kinase 4 (PDK4) expression in muscle. Muscle was a main source of sIL6R, and fat a primary contributor of IL-6 in KPC tumor-bearing mice. Myosteatosis leads to activation of lipid-sensitive kinases like protein kinase C theta (PKCθ, gene name Prkcq) in muscle. KPC tumorbearing mice had increased muscle PKCθ activation, and PKCθ is known to regulate metabolism and inflammation. Prkcq-/- KPC tumor-bearing mice had reduced cachexia and maintained muscle mass and force production versus wild type tumor-bearing mice. Together these data implicate progressive signaling mechanisms whereby tumor-derived IL-6 is associated with increased muscle IL6R expression and fat lipolysis, promoting myosteatosis and muscle PKCθ activation, ultimately increasing cachexia severity in PDAC.
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    Vascular alterations impede fragile tolerance to pregnancy in type 1 diabetes
    (Elsevier, 2022) McNew, Kelsey L.; Abraham, Abin; Sack, Daniel E.; Smart, Charles Duncan; Pettway, Yasminye D.; Falk, Alexander C.; Lister, Rolanda L.; Faucon, Annika B.; Bejan, Cosmin A.; Capra, John A.; Aronoff, David M.; Boyd, Kelli L.; Moore, Daniel J.; Medicine, School of Medicine
    Objective: To determine the impact of autoimmunity in the absence of glycemic alterations on pregnancy in type 1 diabetes (T1D). Design: Because nonobese diabetic (NOD) mice experience autoimmunity before the onset of hyperglycemia, we studied pregnancy outcomes in prediabetic NOD mice using flow cytometry and enzyme-linked immunosorbent assays. Once we determined that adverse events in pregnancy occurred in euglycemic mice, we performed an exploratory study using electronic health records to better understand pregnancy complications in humans with T1D and normal hemoglobin A1c levels. Setting: University Medical Center. Patient(s)/animal(s): Nonobese diabetic mice and electronic health records from Vanderbilt University Medical Center. Intervention(s): Nonobese diabetic mice were administered 200 μg of an anti-interleukin 6 (IL-6) antibody every other day starting on day 5 of gestation. Main outcome measure(s): Changes in the number of abnormal and reabsorbed pups in NOD mice and odds of vascular complications in pregnancy in T1D in relation to A1c. Result(s): Prediabetic NOD mice had increased adverse pregnancy outcomes compared with nonautoimmune mice; blockade of IL-6, which was secreted by endothelial cells, decreased the number of reabsorbed and abnormal fetuses. Similarly, vascular complications were increased in pregnant patients with T1D across all A1c values. Conclusion(s): The vascular secretion of IL-6 drives adverse pregnancy outcomes in prediabetic NOD mice. Pregnant patients with T1D have increased vascular complications even with normal hemoglobin A1cs, indicating a potential effect of autoimmunity on the placental vasculature.