THE ORPHAN RECEPTOR CRF2-4 IS AN ESSENTIAL SUBUNIT OF THE INTERLEUKIN-10 RECEPTOR

The orphan receptor CRF2-4 is a member of the class II cytokine recept or family (CRF2), which includes the interferon receptors, the interle ukin (IL) 10 receptor, and tissue factor. CRFB4, the gene encoding CRF 2-4, is located within a gene cluster on human chromosome 21 that comp rises three interferon receptor subunits. To elucidate the role of CRF 2-4, we disrupted the CRFB4 in mice by means of homologous recombinati on. Mice lacking CRF2-4 show no overt abnormalities, grow normally, an d are fertile. CRF2-4 deficient cells are normally responsive to type I and type II interferons, but lack responsiveness to IL-10. By simila r to 12 wk of age, the majority of mutant mice raised in a conventiona l facility developed a chronic colitis and splenomegaly. Thus, CRFB4 m utant mice recapitulate the phenotype of IL-10-deficient mice. These f indings suggest that CRF2-4 is essential for IL-10-mediated effects an d is a subunit of the IL-10 receptor.