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N-linked glycosylation of IL-13R2 is essential for optimal IL-13 inhibitory activity

Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA

¹Correspondence: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Food and Drug Administration, Center for Biologics Evaluation and Research, NIH Bldg. 29B, Rm. 2NN20, 29 Lincoln Dr., Bethesda, MD 20892 USA. E-mail: raj.puri{at}fda.hhs.gov

ABSTRACT

A high-affinity receptor for interleukin (IL)-13 (interleukin-13R 2) is over-expressed in disease-related fibroblasts and neoplastic cells and is involved in cancer, allergic, and inflammatory diseases. The extracellular domain of IL-13R2 (ECD2) could be cleaved, which serves as a decoy receptor. We have expressed and purified ECD2 in both Escherichia coli (E. coli) and mammalian systems as a soluble fragment and studied its biological activities. Although both products of ECD2 showed IL-13 inhibitory activities, mammalian cell-derived ECD2 appeared to be superior compared with purified protein from E. coli. When expressed in E. coli, ECD2 appeared to be a monomer of 42 but a 60 kDa protein when purified from mammalian cells due to heavy glycosylation. The purified glycosylated ECD2 efficiently inhibited IL-13-induced STAT6 phosphorylation in immune and Hodgkin’s lymphoma cell lines, IL-13 binding, and cytotoxicity of IL-13 cytotoxin in various cancer cell lines. The improved potency of mammalian cell-derived ECD2 was shown over ECD2/Fc fusion protein. The N-linked glycosylation of ECD2 was found to be essential for optimal IL-13 inhibitory activity as deglycosylation by PNGase F showed lower activity. ECD2 did not inhibit IL-4-induced STAT6 phosphorylation, indicating that inhibitory effects of ECD2 are receptor specific. These results indicate that glycosylated ECD2 can serve as a potent inhibitor of IL-13 in a variety of conditions in which IL-13 is a key mediator, e.g., pulmonary, allergic, fibrotic, and neoplastic diseases.—Kioi, M., Seetharam, S., Puri, R. K. N-linked glycosylation of IL-13R2 is essential for optimal IL-13 inhibitory activity.

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