Extracellular ubiquitin inhibits the TNF-α response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical.

Slides:



Advertisements
Similar presentations
IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway  Hee Jung Kim, Seok Bean Song, Jung Min Choi, Kyung Moon Kim,
Advertisements

Volume 63, Issue 2, Pages (February 2003)
The Fumagillin Analogue TNP-470 Inhibits DNA Synthesis of Vascular Smooth Muscle Cells Stimulated by Platelet-Derived Growth Factor and Insulin-like Growth.
IFNα-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity.
MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines by.
IL-1β stimulates CXCL5 and CXCL8 gene expression and protein secretion in A549 cells in a time- and dose-dependent manner. IL-1β stimulates CXCL5 and CXCL8.
by JoAnn Castelli, Elaine K
Antiangiogenic antithrombin down-regulates the expression of the proangiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells by Weiqing.
by Rong He, Hairong Sang, and Richard D. Ye
by Susan E. Shetzline, Ravikumar Rallapalli, Kelley J
Modulation by aspirin of nuclear phospho–signal transducer and activator of transcription 6 expression: Possible role in therapeutic benefit associated.
Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-κB by Lara F. Costa, Mercedes.
Upregulation of Cortactin Expression During the Maturation of Megakaryocytes by Xi Zhan, Christian C. Haudenschild, Yangson Ni, Elizabeth Smith, and Cai.
Activation of JAK2 in Human Vascular Endothelial Cells by Granulocyte-Macrophage Colony-Stimulating Factor by Raffaella Soldi, Luca Primo, Maria Felice.
Effects of inflammatory cytokines on the release and cleavage of the endothelial cell–derived ultralarge von Willebrand factor multimers under flow by.
Presentation of ovalbumin internalized via the immunoglobulin-A Fc receptor is enhanced through Fc receptor γ-chain signaling by Li Shen, Marjolein van.
by Jordi Xaus, Mònica Comalada, Annabel F
Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ by Ingo.
Lipopolysaccharide Activates Caspase-1 (Interleukin-1–Converting Enzyme) in Cultured Monocytic and Endothelial Cells by Ralf R. Schumann, Claus Belka,
Annexin A2 tetramer activates human and murine macrophages through TLR4 by Jennifer F. A. Swisher, Nicholas Burton, Silvia M. Bacot, Stefanie N. Vogel,
Megakaryocyte Growth and Development Factor-Induced Proliferation and Differentiation Are Regulated by the Mitogen-Activated Protein Kinase Pathway in.
Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines by Xiao-Fang.
Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection by Shokrollah Elahi, Toshiro Niki, Mitsuomi Hirashima,
by Rong L. He, Jian Zhou, Crystal Z
by Daniela Buglio, Noor M
Caspases Mediate Tumor Necrosis Factor-–Induced Neutrophil Apoptosis and Downregulation of Reactive Oxygen Production by Kouhei Yamashita, Atsushi Takahashi,
Wanhong Ding, John A. Wagner, Richard D. Granstein 
Volume 71, Issue 6, Pages (March 2007)
Volume 21, Issue 6, Pages (December 2004)
A role for the thiol isomerase protein ERP5 in platelet function
Metalloproteinases Are Involved in Lipopolysaccharide– and Tumor Necrosis Factor-–Mediated Regulation of CXCR1 and CXCR2 Chemokine Receptor Expression.
Circulating forms of intercellular adhesion molecule (ICAM)-1 in mice lacking membranous ICAM-1 by Natasja K. van den Engel, Edmund Heidenthal, Antje Vinke,
Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor κB target genes and induction of apoptosis in chronic.
Yihan Wang, Michael A. Shia, Thomas G. Christensen, Steven C. Borkan 
Chronic neutropenia mediated by Fas ligand
Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies.
Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies by Zhiqing Wang, Yana Zhang, Haichao Liu, Emanuela.
Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone.
Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties by Frederick D. Goldman, Andrew L. Gilman,
Rapid ubiquitination of Syk following GPVI activation in platelets
LPS induces CD40 gene expression through the activation of NF-κB and STAT-1α in macrophages and microglia by Hongwei Qin, Cynthia A. Wilson, Sun Jung Lee,
Platelet-Derived Interleukin-1 Induces Cytokine Production, but not Proliferation of Human Vascular Smooth Muscle Cells by Harald Loppnow, Rosita Bil,
Tumor necrosis factor-α production in whole blood after cardiopulmonary bypass: Downregulation caused by circulating cytokine-inhibitory activities  J.
Interferon- Activates Multiple STAT Proteins and Upregulates Proliferation-Associated IL-2R, c-myc, and pim-1 Genes in Human T Cells by Sampsa Matikainen,
Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival by Kyu-Tae Kim, Kristin Baird, Joon-Young Ahn, Paul.
Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia by Shahrzad Jalali, Tammy Price-Troska, Jonas Paludo, Jose Villasboas, Hyo-Jin.
Shiga toxin 1 elicits diverse biologic responses in mesangial cells
Differential conjugation of endogenous SUMO-1 and endogenous SUMO-2/3 to target proteins.A and B, SUMO-1 and SUMO-2 proteins were produced in E coli and.
Ex vivo IL-6 production. Ex vivo IL-6 production. Human whole blood was stimulated with the indicated doses of the E. coli O113 endotoxin that was used.
Figure 4 Glatiramer acetate treatment negatively regulates IFN-β production by targeting components of the IFN-β enhanceosome (A) Wild-type (WT) monocytes.
1,25-dihydroxyvitamin D3 inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression  Yingjian Li, Bradley C.
Defective negative regulation of Toll-like receptor signaling leads to excessive TNF-α in myeloproliferative neoplasm by Hew Yeng Lai, Stefan A. Brooks,
Anti-Mycotics Suppress Interleukin-4 and Interleukin-5 Production in Anti-CD3 Plus Anti- CD28-Stimulated T Cells from Patients with Atopic Dermatitis 
PPARδ Is a Type 1 IFN Target Gene and Inhibits Apoptosis in T Cells
IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway  Hee Jung Kim, Seok Bean Song, Jung Min Choi, Kyung Moon Kim,
Volume 21, Issue 6, Pages (December 2004)
by Defne Bayik, Debra Tross, Lydia A
IL-12 affects Dermatophagoides farinae–induced IL-4 production by T cells from pediatric patients with mite-sensitive asthma  Takeshi Noma, MD, PhD, Izumi.
Md Nasimuzzaman, Danielle Lynn, Johannes CM van der Loo, Punam Malik 
Volume 22, Issue 1, Pages (January 2005)
Ganglioside GQ1b enhances Ig production by human PBMCs
Dimethylfumarate Induces Immunosuppression via Glutathione Depletion and Subsequent Induction of Heme Oxygenase 1  Joachim C.U. Lehmann, Joanna J. Listopad,
Regulation by Interleukin-10 and Interleukin-4 of Cyclooxygenase-2 Expression in Human Neutrophils by Hiroaki Niiro, Takeshi Otsuka, Kenji Izuhara, Kunihiro.
Figure 2 Glatiramer acetate treatment induced M2 differentiation through a MyD88-independent pathway (A) As described previously,3 M2 monocytes were treated.
Figure 2 Fingolimod impairs induction of activation markers on human monocytes Peripheral blood mononuclear cells from healthy donors were briefly exposed.
John M. Lamar, Vandana Iyer, C. Michael DiPersio 
Figure 3 Fingolimod inhibits TNF-α secretion by human monocytes Peripheral blood mononuclear cells from healthy donors were briefly exposed to increasing.
CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4  Kandace Bonner,
Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti–IL-6 receptor.
CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4  Kandace Bonner,
Presentation transcript:

Extracellular ubiquitin inhibits the TNF-α response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness by Matthias Majetschak, Ulrich Krehmeier, Mark Bardenheuer, Christof Denz, Michael Quintel, Gregor Voggenreiter, and Udo Obertacke Blood Volume 101(5):1882-1890 March 1, 2003 ©2003 by American Society of Hematology

Exogenous ubiquitin inhibits TNF-α secretion of blood and PBMNCs Exogenous ubiquitin inhibits TNF-α secretion of blood and PBMNCs.(A) Dose-dependent inhibition of TNF-α secretion of human whole blood by exogenous ubiquitin. Exogenous ubiquitin inhibits TNF-α secretion of blood and PBMNCs.(A) Dose-dependent inhibition of TNF-α secretion of human whole blood by exogenous ubiquitin. Whole-blood cultures (in duplicates) from healthy donors (n = 13-18) were incubated for 4 hours with 0 to 1 μg/mL exogenous ubiquitin in the presence of 100 ng/mL LPS. Data represent means ± SEM. *P < .05 versus cultures without ubiquitin. (B) Dose-dependent inhibition of TNF-α secretion of human PBMNCs by exogenous ubiquitin. PBMNC cultures (in duplicates) from healthy donors (n = 10-15) were incubated for 4 hours with 0 to 1 μg/mL exogenous ubiquitin in the presence of 100 ng/mL LPS. Data represent means ± SEM. *P < .05 versus cultures without ubiquitin. (C) Kinetics of the LPS-stimulated TNF-α secretion of human whole blood in the presence of 0 (■), 500 ng/mL (▪), and 1000 ng/mL (●) exogenous ubiquitin. Cultures (in duplicates) were incubated for 2, 4, 8, and 16 hours. (D) Kinetics of the LPS-stimulated TNF-α secretion of 105 human PBMNCs in the presence of 0 (■), 500 ng/mL (▪), and 1000 ng/mL (●) exogenous ubiquitin. Cultures (in duplicates) were incubated for 2, 4, 8, and 16 hours. (E) TNF-α mRNA levels in human PBMNCs stimulated with 100 ng/mL LPS in the presence of 0, 500, and 1000 ng/mL ubiquitin for 2 hours. *P < .05 versus stimulation without ubiquitin. (F) Dose-dependent inhibition of TNF-α secretion of porcine (▪) and murine ( ) whole blood by exogenous ubiquitin. Whole-blood cultures (in duplicates; n = 3) were incubated for 4 hours with 0 to 1 μg/mL exogenous ubiquitin in the presence of 100 ng/mL (porcine) and 1 μg/mL (murine) LPS. Data represent means ± SEM. *P < .05 versus cultures without ubiquitin. Matthias Majetschak et al. Blood 2003;101:1882-1890 ©2003 by American Society of Hematology

Effect of exogenous ubiquitin on LPS-induced TNF-α, IL-6, and IL-8 secretion of human whole blood and PBMNCs.Whole blood (▪) and PBMNC ( ) cultures (in duplicates) from healthy donors (n = 3) were incubated for 4 hours and 24 hours with 0 to 1 μg/mL exogeno... Effect of exogenous ubiquitin on LPS-induced TNF-α, IL-6, and IL-8 secretion of human whole blood and PBMNCs.Whole blood (▪) and PBMNC ( ) cultures (in duplicates) from healthy donors (n = 3) were incubated for 4 hours and 24 hours with 0 to 1 μg/mL exogenous ubiquitin in the presence of 100 ng/mL LPS. Data represent means ± SEM. *P < .05 versus cultures without ubiquitin. TNF-α/IL-6/IL-8 production (% control) is percent of TNF-α/IL-6/IL-8 secretion in cultures without exogenous ubiquitin. (A) TNF-α secretion, 4 hours of incubation. (B) TNF-α secretion, 24 hours of incubation. (C) IL-6 secretion, 4 hours of incubation. (D) IL-6 secretion, 24 hours of incubation. (E) IL-8 secretion, 4 hours of incubation. (F) IL-8 secretion, 24 hours of incubation. Matthias Majetschak et al. Blood 2003;101:1882-1890 ©2003 by American Society of Hematology

Detection of ubiquitin in serum and urine Detection of ubiquitin in serum and urine.(A) Ubiquitin serum and urine concentrations in healthy volunteers and critically ill patients. Detection of ubiquitin in serum and urine.(A) Ubiquitin serum and urine concentrations in healthy volunteers and critically ill patients. The boxes extend from the 25th to 75th percentile; the horizontal line shows the median. Error bars show the range of data. Data are measurements of ubiquitin concentrations in serum samples from 35 healthy uninjured donors, 23 severely injured blunt trauma patients on the day of admission, and 24 patients with sepsis. Ubiquitin urine concentrations were determined in specimens from 19 sepsis patients and 10 healthy individuals. *P < .05 versus concentrations in specimens from healthy volunteers. (B) Detection of free ubiquitin in serum specimen by immunoblotting. Serum proteins were separated by SDS-PAGE, transferred to PVDF membranes, and probed for ubiquitin with antiubiquitin AS (1:200). Lane 1, healthy donors' serum (15 μg); lanes 2-5, patients' serum (lane 2, 10 μg; lane 3, 15 μg; lane 4, 20 μg; lane 5, 25 μg); lane 6, ubiquitin (Ub; 10 ng). (C) Detection of free ubiquitin in urine specimen (10 μL) by immunoblotting. Lane 1, ubiquitin (Ub; 5 ng); lane 2, healthy donors' specimen; lanes 3 and 4, patients' specimens. Matthias Majetschak et al. Blood 2003;101:1882-1890 ©2003 by American Society of Hematology

Comparison of ubiquitin serum levels with LPS-stimulated whole blood TNF-α production and neutralization of the inhibitory activity for TNF-α production in patients' serum with antiubiquitin antibody.(A) Ubiquitin serum concentrations in volunteers (n = 12)... Comparison of ubiquitin serum levels with LPS-stimulated whole blood TNF-α production and neutralization of the inhibitory activity for TNF-α production in patients' serum with antiubiquitin antibody.(A) Ubiquitin serum concentrations in volunteers (n = 12) and trauma patients (n = 10) during 14 days after trauma. Data represent means ± SEM. (B) LPS-induced whole blood TNF-α secretion. Volunteers and trauma patients are the same as described in panel A. Whole blood cultures were incubated for 4 hours in the presence of 100 ng/mL LPS. Data represent means ± SEM. (C-D) Antiubiquitin antibodies neutralize the inhibitory activity of ubiquitin on LPS-induced whole blood (C) and PBMNCs (D) TNF-α production. TNF-α production (%) indicates percent of the TNF-α secretion in cultures without exogenous ubiquitin and without antibodies. Data represent means ± SEM from 3 different whole blood and PBMNC cultures obtained from healthy volunteers. Cultures without (■) or with 500 ng/mL exogenous ubiquitin (▪) in the presence of LPS (100 ng/mL for 4 hours). Control indicates cultures without addition of antibody. AS: antiubiquitin AS diluted 1:103, 1:102, and 1:10 in the cell cultures. UbP4D1 and UbN-19: diluted 1:103 in the cell cultures. (E-F) Effect of antiubiquitin antibody on the inhibitory activity of trauma (E) and sepsis (F) patients' serum on LPS-induced TNF-α production of whole blood and PBMNCs. Whole blood (■) and PBMNCs (▪) were cultured with 100 ng/mL LPS for 4 hours. TNF production (%) indicates percent of the TNF-α secretion in cultures containing additional healthy volunteers' serum (30%, vol/vol, in the cell culture mixture) without antibodies. Data represent means ± SEM from 4 different cultures obtained from healthy volunteers. C indicates control, healthy volunteers' serum; TS, trauma patients' serum (n = 4, 30%, vol/vol, in the cell culture mixture); SS, sepsis patients' serum (n = 4, 30%, vol/vol, in the cell culture mixture). Antiubiquitin AS diluted 1:102 and 1:10 in the cell cultures. UbP4D1 and UbN19 were diluted 1:103 in the cell cultures. Matthias Majetschak et al. Blood 2003;101:1882-1890 ©2003 by American Society of Hematology

Endogenous ubiquitin regulates the inhibitory activity for TNF-α production in trauma patients' serum.(A) Trauma patients' serum was applied to an antiubiquitin antibody column and the adsorbed protein was eluted by acidification. Endogenous ubiquitin regulates the inhibitory activity for TNF-α production in trauma patients' serum.(A) Trauma patients' serum was applied to an antiubiquitin antibody column and the adsorbed protein was eluted by acidification. Run-through and elutions were collected and tested for inhibitory activity of LPS-induced TNF-α production in healthy donors' whole blood. Whole blood cultures were incubated with the fractions (50%, vol/vol, in the cell culture mixtures) obtained by affinity chromatography in the presence of LPS for 4 hours in a constant volume of 200 μL. Data (percent control) are means ± SD of the TNF-α secretion in the cell culture supernatants from 2 experiments (in duplicates). C indicates control cell culture in the presence of 25% additional volunteers' serum in a constant volume of 200 μL; TS, cell culture in the presence of 25% trauma patients' serum in a constant volume of 200 μL; RT, cell cultures containing the run-through fraction. pH 7 to pH 3, cell cultures containing the eluted fractions. (B) Immunoblot analysis of the fractions obtained by antiubiquitin affinity chromatography. Fractions were separated by SDS-PAGE, transferred to PVDF membranes, and probed for ubiquitin with antiubiquitin AS (1:200; lanes 1-4) and monoclonal UbP4D1 (1:500; lanes 5-8). Lane 1, patients' serum, 10 μg; lane 2, run-through, 20 μg; lane 3, pH 3/4 eluate, 20 μL; lane 4, ubiquitin, 10 ng; lane 5, patients' serum, 50 μg; lane 6, run-through, 50 μg; lane 7, pH3/4 eluate, 200 μL, pH3/4 eluate 10-fold concentrated by boiling; lane 8, ubiquitin 80 ng. Matthias Majetschak et al. Blood 2003;101:1882-1890 ©2003 by American Society of Hematology

Antiubiquitin antibodies restore reduced TNF-α–producing capacities in blood from trauma and sepsis patients.(A-B) Effect of antiubiquitin antibodies on LPS-induced TNF-α secretion in blood of multiply-injured (A) and sepsis (B) patients. Antiubiquitin antibodies restore reduced TNF-α–producing capacities in blood from trauma and sepsis patients.(A-B) Effect of antiubiquitin antibodies on LPS-induced TNF-α secretion in blood of multiply-injured (A) and sepsis (B) patients. Whole blood was incubated with LPS (100 ng/mL) for 4 hours. AS indicates antiubiquitin AS diluted 1:102 and 1:10 in the cell cultures; UbP4D1 and Ub N19, diluted 1:103 in the cell cultures; volunteers, whole blood cultures from healthy donors; TNF production (%), percent of the TNF-α secretion in trauma (A) and sepsis (B) patients' whole blood incubated without antibodies. Values are mean ± SEM from 5 healthy donors, 5 trauma patients, and 5 sepsis patients. (C) Effect of antiubiquitin AS (1:10) on LPS-induced TNF-α secretion in blood of uninjured donor and trauma and sepsis patients. Individual values from panels A and B. Data are pg/mL TNF-α. Matthias Majetschak et al. Blood 2003;101:1882-1890 ©2003 by American Society of Hematology