Abstract
Tumor necrosis factor (TNF) activates pro-inflammatory functions of vascular endothelial cells (EC) through binding to receptor type 1 (TNFR1) molecules expressed on the cell surface. The majority of TNFR1 molecules are localized to the Golgi apparatus. Soluble forms of TNFR1 (as well as of TNFR2) can be shed from the EC surface and inhibit TNF actions. The relationships among cell surface, Golgi-associated, and shed forms of TNFR1 are unclear. Here we report that histamine causes transient loss of surface TNFR1, TNFR1 shedding, and mobilization of TNFR1 molecules from the Golgi in cultured human EC. The Golgi pool of TNFR1 serves both to replenish cell surface receptors and as a source of shed receptor. Histamine-induced shedding is blocked by TNF-alpha protease inhibitor, an inhibitor of TNF-alpha-converting enzyme, and through the H1 receptor via a MEK-1/p42 and p44 mitogen-activated protein kinase pathway. Cultured EC with histamine-induced surface receptor loss become transiently refractory to TNF. Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Animals
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Brefeldin A / pharmacology
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Cell Membrane / metabolism*
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Cell Separation
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Cells, Cultured
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Dose-Response Relationship, Drug
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Golgi Apparatus / metabolism
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Histamine / metabolism*
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Humans
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I-kappa B Proteins / metabolism
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Immunoblotting
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Immunohistochemistry
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Metalloendopeptidases / metabolism
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Mice
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Microscopy, Confocal
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Microscopy, Electron
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Microscopy, Fluorescence
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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NF-KappaB Inhibitor alpha
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Nitric Oxide Synthase / antagonists & inhibitors
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Skin / metabolism
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Time Factors
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Enzyme Inhibitors
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I-kappa B Proteins
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NFKBIA protein, human
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Nfkbia protein, mouse
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Brefeldin A
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Histamine
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Nitric Oxide Synthase
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein