The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion

• Christian Hundhausen

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Dominika Misztela

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Theo A. Berkhout

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Neil Broadway

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Paul Saftig

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Karina Reiss

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Dieter Hartmann

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Falk Fahrenholz

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Rolf Postina

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Vance Matthews

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Karl-Josef Kallen

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Stefan Rose-John

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

• Andreas Ludwig

  From the Biochemical Institute, Christian-Albrechts-University, Kiel, Germany; Department of Atherosclerosis, GlaxoSmithKline, Stevenage, United Kingdom; Department of Gene Expression & Protein Biochemistry, GlaxoSmithKline, Stevenage, United Kingdom; Center for Human Genetics, Leuven and Flanders Interuniversity, Belgium; and Institute for Biochemistry, Johannes Gutenberg-University, Mainz, Germany.

抄録

The CX3C chemokine fractalkine (CX3CL1) exists as a membrane-expressed protein promoting cell-cell adhesion and as a soluble molecule inducing chemotaxis. Transmembrane CX3CL1 is converted into its soluble form by defined proteolytic cleavage (shedding), which can be enhanced by stimulation with phorbol-12-myristate-13-acetate (PMA). PMA-induced CX3CL1 shedding has been shown to involve the tumor necrosis factor-α–converting enzyme (TACE), whereas the constitutive cleavage in unstimulated cells remains elusive. Here we demonstrate a role of the closely related disintegrin-like metalloproteinase 10 (ADAM10) in the constitutive CX3CL1 cleavage. The hydroxamate GW280264X, capable of blocking TACE as well as ADAM10, proved to be an effective inhibitor of the constitutive and the PMA-inducible CX3CL1 cleavage in CX3CL1-expressing ECV-304 cells (CX3CL1–ECV-304), whereas GI254023X, preferentially blocking ADAM10 but not TACE, reduced the constitutive cleavage only. Overexpression of ADAM10 in COS-7 cells enhanced constitutive cleavage of CX3CL1 and, more importantly, in murine fibroblasts deficient of ADAM10 constitutive CX3CL1 cleavage was markedly reduced. Thus, ADAM10 contributes to the constitutive shedding of CX3CL1 in unstimulated cells. Addressing the functional role of CX3CL1 shedding for the adhesion of monocytic cells via membrane-expressed CX3CL1, we found that THP-1 cells adhere to CX3CL1–ECV-304 cells but detach in the course of vigorous washing. Inhibition of ADAM10-mediated CX3CL1 shedding not only increased adhesive properties of CX3CL1–ECV-304 cells but also prevented de-adhesion of bound THP-1 cells. Our data demonstrate that ADAM10 is involved in the constitutive cleavage of CX3CL1 and thereby may regulate the recruitment of monocytic cells to CX3CL1-expressing cell layers.

収録刊行物

• Blood

  Blood 102 (4), 1186-1195, 2003-08-15

  American Society of Hematology

詳細情報

• CRID: 1363951794842374144
• NII論文ID: 30022496077
• DOI: 10.1182/blood-2002-12-3775
• ISSN: 15280020
• ISSN: 00064971
• ISSN: http://id.crossref.org/issn/00064971
• Web Site: http://ashpublications.org/blood/article-pdf/102/4/1186/1689843/h81603001186.pdf
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