The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10
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The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. / Abel, Soeren; Hundhausen, Christian; Mentlein, Rolf; Schulte, Alexander; Berkhout, Theo A; Broadway, Neil; Hartmann, Dieter; Sedlacek, Radek; Dietrich, Sebastian; Muetze, Barbara; Schuster, Bjoern; Kallen, Karl-Josef; Saftig, Paul; Rose-John, Stefan; Ludwig, Andreas.
In: J IMMUNOL, Vol. 172, No. 10, 15.05.2004, p. 6362-72.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10
AU - Abel, Soeren
AU - Hundhausen, Christian
AU - Mentlein, Rolf
AU - Schulte, Alexander
AU - Berkhout, Theo A
AU - Broadway, Neil
AU - Hartmann, Dieter
AU - Sedlacek, Radek
AU - Dietrich, Sebastian
AU - Muetze, Barbara
AU - Schuster, Bjoern
AU - Kallen, Karl-Josef
AU - Saftig, Paul
AU - Rose-John, Stefan
AU - Ludwig, Andreas
PY - 2004/5/15
Y1 - 2004/5/15
N2 - The novel CXC-chemokine ligand 16 (CXCL16) functions as transmembrane adhesion molecule on the surface of APCs and as a soluble chemoattractant for activated T cells. In this study, we elucidate the mechanism responsible for the conversion of the transmembrane molecule into a soluble chemokine and provide evidence for the expression and shedding of CXCL16 by fibroblasts and vascular cells. By transfection of human and murine CXCL16 in different cell lines, we show that soluble CXCL16 is constitutively generated by proteolytic cleavage of transmembrane CXCL16 resulting in reduced surface expression of the transmembrane molecule. Inhibition experiments with selective hydroxamate inhibitors against the disintegrin-like metalloproteinases a disintegrin and metalloproteinase domain (ADAM)10 and ADAM17 suggest that ADAM10, but not ADAM17, is involved in constitutive CXCL16 cleavage. In addition, the constitutive cleavage of transfected human CXCL16 was markedly reduced in embryonic fibroblasts generated from ADAM10-deficient mice. By induction of murine CXCL16 in ADAM10-deficient fibroblasts with IFN-gamma and TNF-alpha, we show that endogenous ADAM10 is indeed involved in the release of endogenous CXCL16. Finally, the shedding of endogenous CXCL16 could be reconstituted by retransfection of ADAM10-deficient cells with ADAM10. Analyzing the expression and release of CXCXL16 by cultured vascular cells, we found that IFN-gamma and TNF-alpha synergize to induce CXCL16 mRNA. The constitutive shedding of CXCL16 from the endothelial cell surface is blocked by inhibitors of ADAM10 and is independent of additional inhibition of ADAM17. Hence, during inflammation in the vasculature, ADAM10 may act as a CXCL16 sheddase and thereby finely control the expression and function of CXCL16 in the inflamed tissue.
AB - The novel CXC-chemokine ligand 16 (CXCL16) functions as transmembrane adhesion molecule on the surface of APCs and as a soluble chemoattractant for activated T cells. In this study, we elucidate the mechanism responsible for the conversion of the transmembrane molecule into a soluble chemokine and provide evidence for the expression and shedding of CXCL16 by fibroblasts and vascular cells. By transfection of human and murine CXCL16 in different cell lines, we show that soluble CXCL16 is constitutively generated by proteolytic cleavage of transmembrane CXCL16 resulting in reduced surface expression of the transmembrane molecule. Inhibition experiments with selective hydroxamate inhibitors against the disintegrin-like metalloproteinases a disintegrin and metalloproteinase domain (ADAM)10 and ADAM17 suggest that ADAM10, but not ADAM17, is involved in constitutive CXCL16 cleavage. In addition, the constitutive cleavage of transfected human CXCL16 was markedly reduced in embryonic fibroblasts generated from ADAM10-deficient mice. By induction of murine CXCL16 in ADAM10-deficient fibroblasts with IFN-gamma and TNF-alpha, we show that endogenous ADAM10 is indeed involved in the release of endogenous CXCL16. Finally, the shedding of endogenous CXCL16 could be reconstituted by retransfection of ADAM10-deficient cells with ADAM10. Analyzing the expression and release of CXCXL16 by cultured vascular cells, we found that IFN-gamma and TNF-alpha synergize to induce CXCL16 mRNA. The constitutive shedding of CXCL16 from the endothelial cell surface is blocked by inhibitors of ADAM10 and is independent of additional inhibition of ADAM17. Hence, during inflammation in the vasculature, ADAM10 may act as a CXCL16 sheddase and thereby finely control the expression and function of CXCL16 in the inflamed tissue.
KW - ADAM Proteins
KW - Amyloid Precursor Protein Secretases
KW - Animals
KW - COS Cells
KW - Cell Line, Tumor
KW - Cell Membrane
KW - Cells, Cultured
KW - Chemokine CXCL6
KW - Chemokines, CXC
KW - Cytokines
KW - Disintegrins
KW - Endopeptidases
KW - Endothelium, Vascular
KW - Humans
KW - Hydrolysis
KW - Interferon-gamma
KW - Membrane Proteins
KW - Metalloendopeptidases
KW - Mice
KW - Mice, Knockout
KW - Muscle, Smooth, Vascular
KW - Protein Precursors
KW - Protein Structure, Tertiary
KW - Receptors, Immunologic
KW - Receptors, Scavenger
KW - Solubility
KW - Tetradecanoylphorbol Acetate
KW - Tumor Necrosis Factor-alpha
M3 - SCORING: Journal article
C2 - 15128827
VL - 172
SP - 6362
EP - 6372
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 10
ER -