The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli.

Qiao H, Liu Y, Veach RA, Wylezinski L, Hawiger J
J Biol Chem. 2014 289 (32): 21973-83

PMID: 24958727 · PMCID: PMC4139214 · DOI:10.1074/jbc.M114.588723

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.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (20)

Adaptor Proteins, Signal Transducing Animals B-Cell CLL-Lymphoma 10 Protein Capillary Permeability CARD Signaling Adaptor Proteins Cell-Penetrating Peptides Cells, Cultured CRADD Signaling Adaptor Protein Endothelial Cells Humans Human Umbilical Vein Endothelial Cells Inflammation Inflammation Mediators Lung Mice Mice, 129 Strain Microvessels Recombinant Proteins RNA, Small Interfering Signal Transduction

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