title: The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli.
abstract: A hallmark of inflammation, increased vascular permeability, is induced in endothelial cells by multiple agonists through stimulus-coupled assembly of the CARMA3 signalosome, which contains the adaptor protein BCL10. Previously, we reported that BCL10 in immune cells is targeted by the "death" adaptor CRADD/RAIDD (CRADD), which negatively regulates nuclear factor κB (NFκB)-dependent cytokine and chemokine expression in T cells (Lin, Q., Liu, Y., Moore, D. J., Elizer, S. K., Veach, R. A., Hawiger, J., and Ruley, H. E. (2012) J. Immunol. 188, 2493-2497). This novel anti-inflammatory CRADD-BCL10 axis prompted us to analyze CRADD expression and its potential anti-inflammatory action in non-immune cells. We focused our study on microvascular endothelial cells because they play a key role in inflammation. We found that CRADD-deficient murine endothelial cells display heightened BCL10-mediated expression of the pleotropic proinflammatory cytokine IL-6 and chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) in response to LPS and thrombin. Moreover, these agonists also induce significantly increased permeability in cradd(-/-), as compared with cradd(+/+), primary murine endothelial cells. CRADD-deficient cells displayed more F-actin polymerization with concomitant disruption of adherens junctions. In turn, increasing intracellular CRADD by delivery of a novel recombinant cell-penetrating CRADD protein (CP-CRADD) restored endothelial barrier function and suppressed the induction of IL-6 and MCP-1 evoked by LPS and thrombin. Likewise, CP-CRADD enhanced barrier function in CRADD-sufficient endothelial cells. These results indicate that depletion of endogenous CRADD compromises endothelial barrier function in response to inflammatory signals. Thus, we define a novel function for CRADD in endothelial cells as an inducible suppressor of BCL10, a key mediator of responses to proinflammatory agonists.
authors: From the Departments of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine and.
authors: Huan
authors: H
authors: Qiao
authors: From the Departments of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine and.
authors: Yan
authors: Y
authors: Liu
authors: From the Departments of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine and.
authors: Ruth A
authors: RA
authors: Veach
authors: Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors: Lukasz
authors: L
authors: Wylezinski
authors: From the Departments of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232 jacek.hawiger@vanderbilt.edu.
authors: Jacek
authors: J
authors: Hawiger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D053420:CRADD Signaling Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability; D057846:Cell-Penetrating Peptides / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000098:blood supply; D051379:Mice; D057507:Mice, 129 Strain; D055806:Microvessels / Q000166:cytology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; D053420:CRADD Signaling Adaptor Protein; C104252:CRADD protein, human; C498975:Card10 protein, mouse; D057846:Cell-Penetrating Peptides; C484481:Cradd protein, mouse; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D011994:Recombinant Proteins
keywords: BCL10; CARMA3 Signalosome; CRADD; Cytokines/Chemokines; Endothelial Cell; Inflammation; Intracellular Delivery; Lipopolysaccharide (LPS); Permeability; Thrombin