title: Proteolytic Cleavage Governs Interleukin-11 Trans-signaling.
abstract: Interleukin (IL)-11 has been shown to be a crucial factor for intestinal tumorigenesis, lung carcinomas, and asthma. IL-11 is thought to exclusively mediate its biological functions through cell-type-specific expression of the membrane-bound IL-11 receptor (IL-11R). Here, we show that the metalloprotease ADAM10, but not ADAM17, can release the IL-11R ectodomain. Chimeric proteins of the IL-11R and the IL-6 receptor (IL-6R) revealed that a small juxtamembrane portion is responsible for this substrate specificity of ADAM17. Furthermore, we show that the serine proteases neutrophil elastase and proteinase 3 can also cleave the IL-11R. The resulting soluble IL-11R (sIL-11R) is biologically active and binds IL-11 to activate cells. This IL-11 trans-signaling pathway can be inhibited specifically by the anti-inflammatory therapeutic compound sgp130Fc. In conclusion, proteolysis of the IL-11R represents a molecular switch that controls the IL-11 trans-signaling pathway and widens the number of cells that can be activated by IL-11.
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Lokau
authors.affiliation: Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nitz
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Agthe
authors.affiliation: Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Monhasery
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Samadhi
authors.initials: S
authors.lastname: Aparicio-Siegmund
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Neele
authors.initials: N
authors.lastname: Schumacher
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Möller-Hackbarth
authors.affiliation: CONARIS Research Institute AG, 24118 Kiel, Germany.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany. Electronic address: jscheller@uni-duesseldorf.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Institute of Biochemistry, Kiel University, 24098 Kiel, Germany. Electronic address: cgarbers@biochem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000276:immunology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D017370:Interleukin-11 / Q000235:genetics / Q000276:immunology*; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D053146:Myeloblastin / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D059748:Proteolysis; D053702:Receptors, Interleukin-11 / Q000235:genetics / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000893:Anti-Inflammatory Agents; C508611:IL11 protein, human; D017370:Interleukin-11; D008565:Membrane Proteins; D053702:Receptors, Interleukin-11; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases; D019272:Leukocyte Elastase; D053146:Myeloblastin; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C519852:olamkicept
keywords: ADAM10; ADAM17; interleukin-11; proteolysis; signal transduction