Identification, Cloning, and Characterization of a Novel Soluble Receptor That Binds IL-22 and Neutralizes Its Activity
Abstract
With the use of a partial sequence of the human genome, we identified a gene encoding a novel soluble receptor belonging to the class II cytokine receptor family. This gene is positioned on chromosome 6 in the vicinity of the IFNGR1 gene in a head-to-tail orientation. The gene consists of six exons and encodes a 231-aa protein with a 21-aa leader sequence. The secreted mature protein demonstrates 34% amino acid identity to the extracellular domain of the IL-22R1 chain. Cross-linking experiments demonstrate that the protein binds IL-22 and prevents binding of IL-22 to the functional cell surface IL-22R complex, which consists of two subunits, the IL-22R1 and the IL-10R2c chains. Moreover, this soluble receptor, designated IL-22-binding protein (BP), is capable of neutralizing IL-22 activity. In the presence of the IL-22BP, IL-22 is unable to induce Stat activation in IL-22-responsive human lung carcinoma A549 cells. IL-22BP also blocked induction of the suppressors of cytokine signaling-3 (SOCS-3) gene expression by IL-22 in HepG2 cells. To further evaluate IL-22BP action, we used hamster cells expressing a modified IL-22R complex consisting of the intact IL-10R2c and the chimeric IL-22R1/γR1 receptor in which the IL-22R1 intracellular domain was replaced with the IFN-γR1 intracellular domain. In these cells, IL-22 activates biological activities specific for IFN-γ, such as up-regulation of MHC class I Ag expression. The addition of IL-22BP neutralizes the ability of IL-22 to induce Stat activation and MHC class I Ag expression in these cells. Thus, the soluble receptor designated IL-22BP inhibits IL-22 activity by binding IL-22 and blocking its interaction with the cell surface IL-22R complex.
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IL-22 mediates its functions by binding to its heterodimeric receptor consisting of IL-10 receptor β2 (IL-10Rβ2) and IL-22 receptor (IL-22R) and activating signaling pathways that stimulate STAT3 phosphorylation and nuclear translocation.
“IL-22 mediates its functions by binding to its heterodimeric receptor consisting of IL-10 receptor β2 (IL-10Rβ2) and IL-22 receptor (IL-22R) and activating signaling pathways, which stimulate STAT3 phosphorylation and nuclear translocation.80–84”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [82]
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- Authors
- Kotenko, S. V., Izotova, L. S., Mirochnitchenko, O. V., Esterova, E., Dickensheets, H., Donnelly, R. P., & Pestka, S.
- Affiliations
- Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry, Robert Wood Johnson Medical School , Piscataway, NJ 08854
- Center for Biologics Evaluation and Research (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-06
- Volume
- 166
- Issue
- 12
- Pages
- 7096-7103
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1938903801
- Cited by
- 260
- References
- 32
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 10 · 2023: 12 · 2022: 6 · 2021: 15 · 2020: 16 · 2019: 10 · 2018: 19 · 2017: 11 · 2016: 14 · 2015: 12 · 2014: 11 · 2013: 12 · 2012: 10
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (1P30-CA72720, R01 CA-46465, R01CA046465, P30CA072720)
- National Institute of Allergy and Infectious Diseases (R01-AI43369, R01-AI36450, R01AI043369, R01AI036450)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- soluble receptor, IL-22, STAT activation, SOCS3, MHC class I expression, IFNGR1, chromosome 6, gene cloning
- MeSH terms
- Interleukin-22, Amino Acid Sequence, Animals, Base Sequence, Binding, Competitive, Carrier Proteins, Cloning, Molecular, Cricetinae, Humans, Interleukins, Ligands, Molecular Sequence Data, Receptors, Cell Surface, Solubility, Tumor Cells, Cultured, CHO Cells, DNA, Complementary, Receptors, Interleukin, COS Cells
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