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ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23

Nature Immunology volume 7, pages 1293–1298 (2006)Cite this article

Abstract

CD23, the low-affinity immunoglobulin E receptor, is an important modulator of the allergic response and of diseases such as rheumatoid arthritis. The proteolytic release of CD23 from cells is considered a key event in the allergic response. Here we used loss-of-function and gain-of-function experiments with cells lacking or overexpressing candidate CD23-releasing enzymes (ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19 and ADAM33), ADAM-knockout mice and a selective inhibitor to identify ADAM10 as the main CD23-releasing enzyme in vivo. Our findings provide a likely target for the treatment of allergic reactions and set the stage for further studies of the involvement of ADAM10 in CD23-dependent pathologies.

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Figure 1: Shedding of CD23 in wild-type and ADAM-deficient MEFs.
Figure 2: Characterization of candidate CD23 sheddases in wild-type and Adam10−/− MEFs.
Figure 3: Nondefective CD23 shedding in Adam8−/−, Adam9−/−Adam15−/− or Adam9−/−Adam12−/−Adam15−/− mice.
Figure 4: GI254023X blocks constitutive and enhanced CD23 shedding.

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Acknowledgements

We thank V. Nikolenko and A. Shirazi for technical assistance; recombinant mouse IL-4 was a gift from W. Paul (US National Institutes of Health). Supported by the US National Institutes of Health (GM64750 to C.P.B and AI18697 to D.H.C.), the US National Institute of Allergy and Infectious Diseases (T32 AI07407 to J.W.F.) and the National Institutes of Health National Center for Research Resources Research Facilities Improvement Program (C06-RR12538-01 for construction of the facility housing the laboratory of C.P.B.).

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Author notes

  1. Gisela Weskamp and Jill W Ford: These authors contributed equally to this work.

Authors and Affiliations

  1. Hospital for Special Surgery and Departments of Medicine and of Physiology and Biophysics, Arthritis and Tissue Degeneration Program, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Gisela Weskamp, Steven Swendeman & Carl P Blobel

  2. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, 23298, Virginia, USA

    Jill W Ford, Jamie Sturgill & Daniel H Conrad

  3. Discovery Research, GlaxoSmithKline, SG1 2NY, Stevenage, UK

    Steve Martin & Neil Broadway

  4. UCB Celltech, Slough, SL1 4EN, UK

    Andrew J P Docherty

  5. Department for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), Leuven, 3000, Belgium

    Dieter Hartmann

  6. Biochemical Institute, Christian-Albrechts University, Kiel, D-24089, Germany

    Paul Saftig

  7. Schering Plough Research Institute, Kenilworth, 07033, New Jersey, USA

    Shelby Umland

  8. Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan

    Atsuko Sehara-Fujisawa

  9. Amgen, Seattle, Washington, 98119, USA

    Roy A Black

  10. Institute for Molecular Cardiovascular Research, Rhein-Westphalian Technical University, Aachen, D-52056, Germany

    Andreas Ludwig

  11. Department of Biochemical and Analytical Pharmacology, GlaxoSmithKline, Research Triangle Park, 27709, North Carolina, USA

    J David Becherer

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Contributions

G.W., J.W.F., J.S, D.H.C and C.P.B. contributed to the experimental design, data analysis, critical discussions and manuscript preparation; G.W. did the experiments in Figures 1 and 2, the immunoblot in Figure 3c and the titration of the GI254023X inhibitor in Figure 4e for EGF in MEFs; J.W.F prepared and purified antibody 19G5 and did the experiments in Figures 3a,b and 4a–d; J.S. tested how GI254023X affects CD23 shedding from RPMI 8866 cells and primary human tonsillar B cells (Fig. 4e); S.M. and N.B. provided antibody 30X, which both had characterized before, and critical information for its use in Figures 1 and 2; ADAM-deficient mice were supplied by A.J.P.D. (Adam8−/−), A.S.-F. (Adam12−/−) and R.A.B. (Adam17−/−); Adam10−/−, Adam10+/−, wild-type control cells and mouse ADAM10 cDNA were from P.S. and D.H.; Adam33−/− cells and wild-type controls were from S.U.; S.S. injected wild-type and ADAM-deficient mice with antibody 19G5, isolated serum and collected spleens for the experiments in Figure 3a,b; A.L. and J.D.B provided GI254023X and BB94; J.D.B. provided information and discussions, especially at beginning; D.H.C and C.P.B supervised this study; and all authors contributed to the final stages of manuscript preparation.

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Correspondence to Carl P Blobel.

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Competing interests

A.D., N.B., S.U., R.A.B. and J.D.B. are employed by pharmaceutical companies. Antibody 30X is the subject of patent WO 99/58679 (“Antibodies to CD23, derivatives thereof, and their therapeutic uses”).

Supplementary information

Supplementary Fig. 1

Generation of the humanized CD23 mAb 30X and specificity control. (PDF 934 kb)

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Weskamp, G., Ford, J., Sturgill, J. et al. ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23. Nat Immunol 7, 1293–1298 (2006). https://doi.org/10.1038/ni1399

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