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Cytokine-mediated changes in K channel activity promotes an adaptive Ca response that sustains β-cell insulin secretion during inflammation.
Dickerson MT, Bogart AM, Altman MK, Milian SC, Jordan KL, Dadi PK, Jacobson DA
(2018) Sci Rep 8: 1158
MeSH Terms: Adult, Animals, Calcium, Female, Gene Expression Regulation, Glucose, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Interferon-gamma, Interleukin-1beta, Ion Transport, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Potassium, Potassium Channels, Tandem Pore Domain, Primary Cell Culture, RNA, Messenger, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Tissue Culture Techniques, Tumor Necrosis Factor-alpha
Show Abstract · Added February 7, 2018
Cytokines present during low-grade inflammation contribute to β-cell dysfunction and diabetes. Cytokine signaling disrupts β-cell glucose-stimulated Ca influx (GSCI) and endoplasmic reticulum (ER) Ca ([Ca]) handling, leading to diminished glucose-stimulated insulin secretion (GSIS). However, cytokine-mediated changes in ion channel activity that alter β-cell Ca handling remain unknown. Here we investigated the role of K currents in cytokine-mediated β-cell dysfunction. K currents, which control the termination of intracellular Ca ([Ca]) oscillations, were reduced following cytokine exposure. As a consequence, [Ca] and electrical oscillations were accelerated. Cytokine exposure also increased basal islet [Ca] and decreased GSCI. The effect of cytokines on TALK-1 K currents were also examined as TALK-1 mediates K by facilitating [Ca] release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca] storage while maintaining 2 phase GSCI and GSIS. This adaptive Ca response was absent in TALK-1 KO islets, which exhibited decreased 2 phase GSCI and diminished GSIS. These findings suggest that K and TALK-1 currents play important roles in altered β-cell Ca handling and electrical activity during low-grade inflammation. These results also reveal that a cytokine-mediated reduction in TALK-1 serves an acute protective role in β-cells by facilitating increased Ca content to maintain GSIS.
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25 MeSH Terms
A New Role of Mister (MR) T in Hypertension: Mineralocorticoid Receptor, Immune System, and Hypertension.
Barbaro NR, Kirabo A, Harrison DG
(2017) Circ Res 120: 1527-1529
MeSH Terms: Blood Pressure, Humans, Hypertension, Interferon-gamma, Receptors, Mineralocorticoid, T-Lymphocytes
Added December 27, 2017
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6 MeSH Terms
IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function.
Guo Y, Luan L, Patil NK, Wang J, Bohannon JK, Rabacal W, Fensterheim BA, Hernandez A, Sherwood ER
(2017) J Immunol 198: 1320-1333
MeSH Terms: Animals, Female, Interferon-gamma, Interleukin-15, Killer Cells, Natural, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Shock, Septic
Show Abstract · Added May 10, 2017
Interleukin 15 is essential for the development and differentiation of NK and memory CD8 (mCD8) T cells. Our laboratory previously showed that NK and CD8 T lymphocytes facilitate the pathobiology of septic shock. However, factors that regulate NK and CD8 T lymphocyte functions during sepsis are not well characterized. We hypothesized that IL-15 promotes the pathogenesis of sepsis by maintaining NK and mCD8 T cell integrity. To test our hypothesis, the pathogenesis of sepsis was assessed in IL-15-deficient (IL-15 knockout, KO) mice. IL-15 KO mice showed improved survival, attenuated hypothermia, and less proinflammatory cytokine production during septic shock caused by cecal ligation and puncture or endotoxin-induced shock. Treatment with IL-15 superagonist (IL-15 SA, IL-15/IL-15Rα complex) regenerated NK and mCD8 T cells and re-established mortality of IL-15 KO mice during septic shock. Preventing NK cell regeneration attenuated the restoration of mortality caused by IL-15 SA. If given immediately prior to septic challenge, IL-15-neutralizing IgG M96 failed to protect against septic shock. However, M96 caused NK cell depletion if given 4 d prior to septic challenge and conferred protection. IL-15 SA treatment amplified endotoxin shock, which was prevented by NK cell or IFN-γ depletion. IL-15 SA treatment also exacerbated septic shock caused by cecal ligation and puncture when given after the onset of sepsis. In conclusion, endogenous IL-15 does not directly augment the pathogenesis of sepsis but enables the development of septic shock by maintaining NK cell numbers and integrity. Exogenous IL-15 exacerbates the severity of sepsis by activating NK cells and facilitating IFN-γ production.
Copyright © 2017 by The American Association of Immunologists, Inc.
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10 MeSH Terms
PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation.
Iwata H, Goettsch C, Sharma A, Ricchiuto P, Goh WW, Halu A, Yamada I, Yoshida H, Hara T, Wei M, Inoue N, Fukuda D, Mojcher A, Mattson PC, Barabási AL, Boothby M, Aikawa E, Singh SA, Aikawa M
(2016) Nat Commun 7: 12849
MeSH Terms: ADP-Ribosylation, Animals, Apoptosis, Atherosclerosis, Cell Survival, Coronary Artery Disease, Female, Humans, Inflammation, Interferon-gamma, Interleukin-4, Lipopolysaccharide Receptors, Macrophage Activation, Male, Mice, Mice, Inbred C57BL, Neoplasm Proteins, Phosphorylation, Plaque, Atherosclerotic, Poly(ADP-ribose) Polymerases, RAW 264.7 Cells, RNA Interference, Ribose, STAT1 Transcription Factor, THP-1 Cells
Show Abstract · Added March 14, 2018
Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9-PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation.
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25 MeSH Terms
Flt3 Ligand Treatment Attenuates T Cell Dysfunction and Improves Survival in a Murine Model of Burn Wound Sepsis.
Patil NK, Bohannon JK, Luan L, Guo Y, Fensterheim B, Hernandez A, Wang J, Sherwood ER
(2017) Shock 47: 40-51
MeSH Terms: Animals, Burns, CD28 Antigens, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Disease Models, Animal, Interferon-gamma, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, Sepsis, T-Lymphocytes
Show Abstract · Added December 13, 2016
INTRODUCTION - Sepsis is a leading cause of death among severely burned patients. Burn injury disrupts the protective skin barrier and causes immunological dysfunction. In our previous studies, we found that burn injury and wound infection causes a significant decline in lymphocyte populations, implying adaptive immune system dysfunction. In the present study, we examined the effect of treatment with Fms-like tyrosine kinase-3 Ligand (Flt3L) on T cell phenotype and function in a model of burn wound sepsis. FLt3L is an essential cytokine required for hematopoietic progenitor cell development and expansion of both myeloid and lymphoid lineages. Flt3L has been shown to potentiate innate immune functions of dendritic cells and neutrophils during burn wound sepsis. However, the ability of Flt3L to improve T cell function during burn wound sepsis has not been previously evaluated.
METHODS - Mice underwent 35% total body surface area scald burn and were treated with Flt3L (10 μg) or vehicle daily via the intraperitoneal route starting 1 day after burn injury. On day 4 after burn injury, Pseudomonas aeruginosa was used to induce wound infection. Leukocytes in spleen and wound draining lymph nodes were characterized using flow cytometry. Bacterial clearance, organ injury, and survival were also assessed.
RESULTS - Flt3L treatment prevented the decline in splenic CD4 and CD8 T cells caused by burn injury and infection. Flt3L treatment also attenuated the decline in CD28 expression on CD4 and CD8 T cells and IFNγ production by CD8 T cells in the spleen and wound draining lymph nodes. Furthermore, Flt3L decreased the levels of programmed death ligand 1 expression on splenic dendritic cells and macrophages. Flt3 treatment improved systemic bacterial clearance, decreased liver and kidney injury, and significantly improved survival in mice with burn wound sepsis.
CONCLUSION - Burn injury and associated sepsis causes significant loss of T cells and evidence of T cell dysfunction. Flt3L attenuates T cell dysfunction and improves host resistance to burn wound sepsis in mice.
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13 MeSH Terms
Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice.
Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van Kaer L, Iwabuchi K
(2016) Sci Rep 6: 28473
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adiponectin, Animals, Antigen Presentation, Antigens, CD1d, B7-1 Antigen, Diet, High-Fat, Disease Models, Animal, Disease Progression, Galactosylceramides, Insulin Resistance, Interferon-gamma, Lymphocyte Activation, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells, Obesity
Show Abstract · Added July 30, 2016
It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity.
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21 MeSH Terms
Linking inflammation and hypertension via LNK/SH2B3.
Dale BL, Madhur MS
(2016) Curr Opin Nephrol Hypertens 25: 87-93
MeSH Terms: Animals, Blood Pressure, Dendritic Cells, Humans, Hypertension, Inflammation, Interferon-gamma, Kidney, Proteins
Show Abstract · Added September 7, 2017
PURPOSE OF REVIEW - Hypertension is a leading cause of cardiovascular and renal morbidity, and mortality. Genome-wide association studies identified a single-nucleotide polymorphism in the gene SH2B3 encoding the lymphocyte adaptor protein, LNK, but, until recently, little was known about how LNK contributes to hypertension. This review summarizes recent work highlighting a central role for LNK in inflammation and hypertension.
RECENT FINDINGS - Using a systems biology approach that integrates genomic data with whole blood transcriptomic data and network modeling, LNK/SH2B3 was identified as a key driver gene for hypertension in humans. LNK is an intracellular adaptor protein expressed predominantly in hematopoietic and endothelial cells that negatively regulates cell proliferation and cytokine signaling. Genetic animal models with deletion or mutation of LNK revealed an important role for LNK in renal and vascular inflammation, glomerular injury, oxidative stress, interferon-γ production, and hypertension. Bone marrow transplantation experiments revealed that LNK in hematopoietic cells is primarily responsible for blood pressure regulation.
SUMMARY - LNK/SH2B3 is a key driver gene for human hypertension, and alteration of LNK in animal models has a profound effect on inflammation and hypertension. Thus, LNK is a potential therapeutic target for this disease and its devastating consequences.
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9 MeSH Terms
The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice.
Garay J, Piazuelo MB, Majumdar S, Li L, Trillo-Tinoco J, Del Valle L, Schneider BG, Delgado AG, Wilson KT, Correa P, Zabaleta J
(2016) Cancer Lett 371: 90-8
MeSH Terms: Animals, Antigens, Ly, Cells, Cultured, Chemotaxis, Leukocyte, Disease Models, Animal, Disease Progression, Female, Gastric Mucosa, Gastritis, Atrophic, Helicobacter Infections, Helicobacter pylori, Humans, Hyaluronan Receptors, Interferon-gamma, Macrophages, Peritoneal, Mice, Knockout, Neutrophil Infiltration, Neutrophils, Precancerous Conditions, Signal Transduction, Stomach Neoplasms, Time Factors
Show Abstract · Added February 15, 2016
Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori-positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of 6 years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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22 MeSH Terms
Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries.
Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, Den Boon S, Borroto Gutierrez SM, Bruchfeld J, Burhan E, Cavalcante S, Cedillos R, Chaisson R, Chee CB, Chesire L, Corbett E, Dara M, Denholm J, de Vries G, Falzon D, Ford N, Gale-Rowe M, Gilpin C, Girardi E, Go UY, Govindasamy D, D Grant A, Grzemska M, Harris R, Horsburgh CR, Ismayilov A, Jaramillo E, Kik S, Kranzer K, Lienhardt C, LoBue P, Lönnroth K, Marks G, Menzies D, Migliori GB, Mosca D, Mukadi YD, Mwinga A, Nelson L, Nishikiori N, Oordt-Speets A, Rangaka MX, Reis A, Rotz L, Sandgren A, Sañé Schepisi M, Schünemann HJ, Sharma SK, Sotgiu G, Stagg HR, Sterling TR, Tayeb T, Uplekar M, van der Werf MJ, Vandevelde W, van Kessel F, van't Hoog A, Varma JK, Vezhnina N, Voniatis C, Vonk Noordegraaf-Schouten M, Weil D, Weyer K, Wilkinson RJ, Yoshiyama T, Zellweger JP, Raviglione M
(2015) Eur Respir J 46: 1563-76
MeSH Terms: Antirheumatic Agents, Antitubercular Agents, Coinfection, Comorbidity, Disease Management, Drug Users, Emigrants and Immigrants, Evidence-Based Medicine, HIV Infections, Health Personnel, Homeless Persons, Humans, Interferon-gamma Release Tests, Isoniazid, Kidney Failure, Chronic, Latent Tuberculosis, Mass Screening, Practice Guidelines as Topic, Prisoners, Public Health, Radiography, Thoracic, Renal Dialysis, Rifampin, Risk Assessment, Silicosis, Substance-Related Disorders, Transplant Recipients, Tuberculin Test, Tumor Necrosis Factor-alpha, World Health Organization
Show Abstract · Added February 17, 2016
Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.
Copyright ©ERS 2015.
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30 MeSH Terms
IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.
Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER
(2015) J Immunol 195: 2353-64
MeSH Terms: Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Body Temperature, CD8-Positive T-Lymphocytes, Cell Proliferation, Cytotoxicity, Immunologic, Dose-Response Relationship, Drug, Female, Flow Cytometry, Granzymes, Humans, Interferon-gamma, Interleukin-15, Interleukin-15 Receptor alpha Subunit, Killer Cells, Natural, Lectins, C-Type, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, Perforin
Show Abstract · Added October 18, 2015
IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.
Copyright © 2015 by The American Association of Immunologists, Inc.
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