title: Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding.
abstract: Hypomorphic ADAM17(ex/ex) mice showed defects in mucosal regeneration due to inefficient enhanced GFR shedding. ADAM17 is the main sheddase of interleukin-6 receptor (IL-6R) to induce IL-6 trans-signaling. However, serum levels of soluble murine IL-6R were not reduced in ADAM17(ex/ex) mice, and murine ADAM17 was not the major sheddase of murine IL-6R. Shedding of murine IL-6R by murine ADAM17 was rescued in chimeric murine IL-6R proteins containing any extracellular domain but not the transmembrane and intracellular domain of human IL-6R. Apoptosis is a physiological stimulus of ADAM17-mediated shedding of human IL-6R. Even though apoptosis induced IL-6R shedding in mice, the responsible protease was identified as ADAM10. ADAM10 also was identified as protease responsible for ionomycin-induced shedding of murine and human IL-6R. However, in ADAM10-deficient murine embryonic fibroblasts, compensatory shedding of human IL-6R was mediated by ADAM17, but loss of ADAM10-mediated shedding of murine IL-6R was compensated by an as-yet-unidentified protease. Finally, we identified physiological purinergic P2X7 receptor stimulation as a novel inducer of murine and human IL-6R shedding solely mediated by ADAM10. In conclusion, we describe an unexpected species specificity of ADAM10 and ADAM17 and identified ADAM10 as novel inducible sheddase of IL-6R in mice and humans, which might have consequences for the interpretation of phenotypes from ADAM17- and ADAM10-deficient mice.
authors: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstrasse 40, Kiel, Germany.
authors: Christoph
authors: C
authors: Garbers
authors: Nathalie
authors: N
authors: Jänner
authors: Athena
authors: A
authors: Chalaris
authors: Marcia L
authors: ML
authors: Moss
authors: Doreen M
authors: DM
authors: Floss
authors: Dörte
authors: D
authors: Meyer
authors: Friedrich
authors: F
authors: Koch-Nolte
authors: Stefan
authors: S
authors: Rose-John
authors: Jürgen
authors: J
authors: Scheller
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity
chemical_list: D015850:Interleukin-6; D008565:Membrane Proteins; D019947:Receptors, Interleukin-6; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse