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Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry, Robert Wood Johnson Medical School, Piscataway, NJ 08854; and
Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
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/
R1 receptor in
which the IL-22R1 intracellular domain was replaced with the IFN-R1
intracellular domain. In these cells, IL-22 activates biological
activities specific for IFN-, 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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