Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity

(W)ith the use of a partial sequence of the human genome, we identified a g ene encoding a novel soluble receptor belonging to the class II cytokine re ceptor family. This gene is positioned on chromosome 6 in the vicinity of t he IFNGR1 gene in a head-to-tall orientation. The gene consists of six exon s and encodes a 231-aa protein with a 21-aa leader sequence. The secreted m ature protein demonstrates 34% amino acid identity to the extracellular dom ain of the IL-22R1 chain. Cross-linking experiments demonstrate that the pr otein binds IL-22 and prevents binding of IL-22 to the functional cell surf ace IL-22R complex, which consists of two subunits, the IL-22R1 and the IL- 10R2(c). 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 sup pressors of cytokine signaling-3 (SOCS-3) gene expression by IL-22 in HepG2 cells. To further evaluate IL-22BP action, we used hamster cells expressin g a modified IL-22R complex consisting of the intact IL-10R2(c) and the chi meric IL-22R1/gamma R1 receptor in which the IL-22R1 intracellular domain w as replaced with the IFN-gamma R1 intracellular domain. In these cells, IL- 22 activates biological activities specific for IFN-gamma, such as up-regul ation 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 i n these cells. Thus, the soluble receptor designated IL-22BP inhibits IL-22 activity by binding IL-22 and blocking its interaction with the cell surfa ce IL-22R complex.