Browsing by Subject "cytokine"

Now showing 1 - 7 of 7
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    Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention
    (Elsevier, 2020-02-04) Nakayasu, Ernesto S.; Syed, Farooq; Tersey, Sarah A.; Gritsenko, Marina A.; Mitchell, Hugh D.; Chan, Chi Yuet; Dirice, Ercument; Turatsinze, Jean-Valery; Cui, Yi; Kulkarni, Rohit N.; Eizirik, Decio L.; Qian, Wei-Jun; Webb-Robertson, Bobbie-Jo M.; Evans-Molina, Carmella; Mirmira., Raghavendra G.; Metz, Thomas O.; Pediatrics, School of Medicine
    Type 1 diabetes (T1D) results from the progressive loss of β cells, a process propagated by pro-inflammatory cytokine signaling that disrupts the balance between pro- and anti-apoptotic proteins. To identify proteins involved in this process, we performed comprehensive proteomics of human pancreatic islets treated with interleukin-1β and interferon-γ, leading to the identification of 11,324 proteins, of which 387 were significantly regulated by treatment. We then tested the function of growth/differentiation factor 15 (GDF15), which was repressed by the treatment. We found that GDF15 translation was blocked during inflammation, and it was depleted in islets from individuals with T1D. The addition of exogenous GDF15 inhibited interleukin-1β+interferon-γ-induced apoptosis of human islets. Administration of GDF15 reduced by 53% the incidence of diabetes in NOD mice. Our approach provides a unique resource for the identification of the human islet proteins regulated by cytokines and was effective in discovering a potential target for T1D therapy.
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    High mobility group box 1 protein regulates osteoclastogenesis through direct actions on osteocytes and osteoclasts in vitro
    (Wiley, 2019-05-20) Davis, Hannah M.; Valdez, Sinai; Gomez, Leland; Malicky, Peter; White, Fletcher A.; Subler, Mark A.; Windle, Jolene J.; Bidwell, Joseph P.; Bruzzaniti, Angela; Plotkin, Lilian I.; Anatomy and Cell Biology, School of Medicine
    Old age and Cx43 deletion in osteocytes are associated with increased osteocyte apoptosis and osteoclastogenesis. We previously demonstrated that apoptotic osteocytes release elevated concentrations of the pro-inflammatory cytokine, high mobility group box1 protein (HMGB1) and apoptotic osteocyte conditioned media (CM) promotes osteoclast differentiation. Further, prevention of osteocyte apoptosis blocks osteoclast differentiation and attenuates the extracellular release of HMGB1 and RANKL. Moreover, sequestration of HMGB1, in turn, reduces RANKL production/release by MLO-Y4 osteocytic cells silenced for Cx43 (Cx43def), highlighting the possibility that HMGB1 promotes apoptotic osteocyte-induced osteoclastogenesis. However, the role of HMGB1 signaling in osteocytes has not been well studied. Further, the mechanisms underlying its release and the receptor(s) responsible for its actions is not clear. We now report that a neutralizing HMGB1 antibody reduces osteoclast formation in RANKL/MCSF treated bone marrow cells (BMC). In bone marrow macrophages (BMMs), TLR4 inhibition with LPS-RS, but not RAGE inhibition with Azeliragon attenuated osteoclast differentiation. Further, inhibition of RAGE but not of TLR4 in osteoclast precursors reduced osteoclast number, suggesting that HGMB1 produced by osteoclasts directly effects differentiation by activating TLR4 in BMMs and RAGE in pre-osteoclasts. Our findings also suggest that increased osteoclastogenesis induced by apoptotic osteocytes CM is not mediated through HMGB1/RAGE activation and that direct HMGB1 actions in osteocytes stimulate pro-osteoclastogenic signal release from Cx43def osteocytes. Based on these findings, we propose that HMGB1 exerts dual effects on osteoclasts, directly by inducing differentiation through TLR4 and RAGE activation and indirectly by increasing pro-osteoclastogenic cytokine secretion from osteocytes.
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    Machine Learning to Build and Validate a Model for Radiation Pneumonitis Prediction in Patients with Non–Small Cell Lung Cancer
    (AACR, 2019-07) Yu, Hao; Wu, Huanmei; Wang, Weili; Jolly, Shruti; Jin, Jianyue; Hu, Chen; Kong, Feng-Ming (Spring); BioHealth Informatics, School of Informatics and Computing
    Purpose: Radiation pneumonitis is an important adverse event in patients with non–small cell lung cancer (NSCLC) receiving thoracic radiotherapy. However, the risk of radiation pneumonitis grade ≥ 2 (RP2) has not been well predicted. This study hypothesized that inflammatory cytokines or the dynamic changes during radiotherapy can improve predictive accuracy for RP2. Experimental Design: Levels of 30 inflammatory cytokines and clinical information in patients with stages I–III NSCLC treated with radiotherapy were from our prospective studies. Statistical analysis was used to select predictive cytokine candidates and clinical covariates for adjustment. Machine learning algorithm was used to develop the generalized linear model for predicting risk RP2. Results: A total of 131 patients were eligible and 17 (13.0%) developed RP2. IL8 and CCL2 had significantly (Bonferroni) lower expression levels in patients with RP2 than without RP2. But none of the changes in cytokine levels during radiotherapy was significantly associated with RP2. The final predictive GLM model for RP2 was established, including IL8 and CCL2 at baseline level and two clinical variables. Nomogram was constructed based on the GLM model. The model's predicting ability was validated in the completely independent test set (AUC = 0.863, accuracy = 80.0%, sensitivity = 100%, specificity = 76.5%). Conclusions: By machine learning, this study has developed and validated a comprehensive model integrating inflammatory cytokines with clinical variables to predict RP2 before radiotherapy that provides an opportunity to guide clinicians.
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    Molecular Mechanisms Underlying Osteocyte Apoptosis and the Associated Osteoclastogenesis in CX43-Deficiency and Aging
    (2019-06) Davis, Hannah Marie; Plotkin, Lillian I.; Bidwell, Joseph P.; Allen, Matthew R.; Bruzzaniti, Angela
    Old age is associated with increased bone fragility and risk of fracture as a result of skeletal alterations, including low bone density and cortical thinning. Further, apoptotic osteocytes accumulate in old mice and humans. We have previously shown that mice lacking osteocytic connexin (Cx) 43 (Cx43ΔOt) exhibit a phenotype similar to that of the aging skeleton, with elevated osteocyte apoptosis and an associated increase in osteoclastogenesis. These findings suggest that osteocyte apoptosis results in the release of factors that recruit osteoclasts to bone surfaces close to areas that contain apoptotic osteocytes. However, the specific chemotactic signals, the events mediating their release, and the mechanisms of their action remain unknown. Consistent with this notion, we also found that HMGB1 released by Cx43-deficient (Cx43def) MLO-Y4 osteocytic cells enhances osteoclastogenesis in part by increasing osteocytic RANKL, which promotes osteoclastogenesis, and, at the same time, directly stimulating osteoclastogenesis. Further, expression of the pro-survival microRNA (miR), miR21, is low in Cx43def cells and bones from old female mice, and low miR21 levels increase osteocyte apoptosis. However, surprisingly, mice lacking miR21 (miR21ΔOt) have decreased osteoclast number and activity even under conditions of elevated osteocyte apoptosis; suggesting that osteocytic miR21 may mediate osteoclast precursor recruitment/survival induced by apoptotic osteocytes. However, whether HMGB1/miR21 are released by osteocytes, and if the HMGB1 receptors, receptor for advanced glycation end products (RAGE) and/or tolllike receptor (TLR4) are involved in osteoclast recruitment in Cx43ΔOt and old mice is unknown. The overall objectives of this series of studies were to elucidate the mechanisms
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    Osteocytic miR21 deficiency improves bone strength independent of sex despite having sex divergent effects on osteocyte viability and bone turnover
    (Wiley, 2019-09-18) Davis, Hannah M.; Deosthale, Padmini J.; Pacheco‐Costa, Rafael; Essex, Alyson L.; Atkinson, Emily G.; Aref, Mohammad W.; Dilley, Julian E.; Bellido, Teresita; Ivan, Mircea; Allen, Matthew R.; Plotkin, Lilian I.; Anatomy and Cell Biology, School of Medicine
    Osteocytes play a critical role in mediating cell-cell communication and regulating bone homeostasis, and osteocyte apoptosis is associated with increased bone resorption. miR21, an oncogenic microRNA, regulates bone metabolism by acting directly on osteoblasts and osteoclasts, but its role in osteocytes is not clear. Here, we show that osteocytic miR21 deletion has sex-divergent effects in bone. In females, miR21 deletion reduces osteocyte viability, but suppresses bone turnover. Conversely, in males, miR21 deletion increases osteocyte viability, but stimulates bone turnover and enhances bone structure. Further, miR21 deletion differentially alters osteocyte cytokine production in the two sexes. Interestingly, despite these changes, miR21 deletion increases bone mechanical properties in both sexes, albeit to a greater extent in males. Collectively, our findings suggest that miR21 exerts both sex-divergent and sex-equivalent roles in osteocytes, regulating osteocyte viability and altering bone metabolism through paracrine actions on osteoblasts and osteoclasts differentially in males vs. females, whereas, influencing bone mechanical properties independent of sex.
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    Principal component analysis identifies patterns of cytokine expression in non-small cell lung cancer patients undergoing definitive radiation therapy
    (PLOS, 2017-09-21) Ellsworth, Susannah G.; Rabatic, Bryan M.; Chen, Jie; Zhao, Jing; Campbell, Jeffrey; Wang, Weili; Pi, Wenhu; Stanton, Paul; Matuszak, Martha; Jolly, Shruti; Miller, Amy; Kong, Feng-Ming; Radiation Oncology, School of Medicine
    Background/Purpose Radiation treatment (RT) stimulates the release of many immunohumoral factors, complicating the identification of clinically significant cytokine expression patterns. This study used principal component analysis (PCA) to analyze cytokines in non-small cell lung cancer (NSCLC) patients undergoing RT and explore differences in changes after hypofractionated stereotactic body radiation therapy (SBRT) and conventionally fractionated RT (CFRT) without or with chemotherapy. Methods The dataset included 141 NSCLC patients treated on prospective clinical protocols; PCA was based on the 128 patients who had complete CK values at baseline and during treatment. Patients underwent SBRT (n = 16), CFRT (n = 18), or CFRT (n = 107) with concurrent chemotherapy (ChRT). Levels of 30 cytokines were measured from prospectively collected platelet-poor plasma samples at baseline, during RT, and after RT. PCA was used to study variations in cytokine levels in patients at each time point. Results Median patient age was 66, and 22.7% of patients were female. PCA showed that sCD40l, fractalkine/C3, IP10, VEGF, IL-1a, IL-10, and GMCSF were responsible for most variability in baseline cytokine levels. During treatment, sCD40l, IP10, MIP-1b, fractalkine, IFN-r, and VEGF accounted for most changes in cytokine levels. In SBRT patients, the most important players were sCD40l, IP10, and MIP-1b, whereas fractalkine exhibited greater variability in CFRT alone patients. ChRT patients exhibited variability in IFN-γ and VEGF in addition to IP10, MIP-1b, and sCD40l. Conclusions PCA can identify potentially significant patterns of cytokine expression after fractionated RT. Our PCA showed that inflammatory cytokines dominate post-treatment cytokine profiles, and the changes differ after SBRT versus CFRT, with vs without chemotherapy. Further studies are planned to validate these findings and determine the clinical significance of the cytokine profiles identified by PCA.
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    Whole-Body Vibration Training Increases Stem/Progenitor Cell Circulation Levels and May Attenuate Inflammation
    (Oxford, 2020-01) Jawed, Yameena; Beli, Eleni; March, Keith; Kaleth, Anthony; Loghmani, M Terry; Medicine, School of Medicine
    Introduction Whole-body vibration training (WBVT) may benefit individuals with difficulty participating in physical exercise. The objective was to explore the effects of WBVT on circulating stem/progenitor cell (CPC) and cytokine levels. Methods Healthy male subjects each performed three activities randomly on separate days: (1) standing platform vibration, (2) repetitive leg squat exercise; and (3) in combination. Pre- and post-activity blood samples were drawn. Cell populations were characterized using flow cytometry. Biomarkers were analyzed using enzyme-linked immunosorbent assays. Results CPC levels increased significantly 21% with exercise alone (1465 ± 202–1770 ± 221 cells/mL; P = 0.017) and 33% with vibration alone in younger participants (1918 ± 341–2559 ± 496; P = 0.02). Angiogenic CPCs increased 39% during combined activity in younger (633 ± 128–882 ± 181; P = 0.05). Non-angiogenic CPCs increased 42% with vibration alone in younger (1181 ± 222–1677 ± 342; P = 0.04), but 32% with exercise alone in older participants (801 ± 251–1053 ± 325; P = 0.05). With vibration alone, anti-inflammatory cytokine interleukin-10 increased significantly (P < 0.03), although inflammatory interleukin-6 decreased (P = 0.056); tumor necrosis factor-alpha (P < 0.01) and vascular endothelial growth factor levels increased (P < 0.005), which are synergistically pro-angiogenic. Conclusions WBVT may have positive vascular and anti-inflammatory effects. WBVT could augment or serve as an exercise surrogate in warfighters and others who cannot fully participate in exercise programs, having important implications in military health.