The Orphan Receptor CRF2-4 Is an Essential Subunit of the Interleukin 10 Receptor

Abstract

The orphan receptor CRF2-4 is a member of the class II cytokine receptor family (CRF2), which includes the interferon receptors, the interleukin (IL) 10 receptor, and tissue factor. CRFB4, the gene encoding CRF2-4, is located within a gene cluster on human chromosome 21 that comprises three interferon receptor subunits. To elucidate the role of CRF2-4, we disrupted the CRFB4 gene in mice by means of homologous recombination. Mice lacking CRF2-4 show no overt abnormalities, grow normally, and are fertile. CRF2-4 deficient cells are normally responsive to type I and type II interferons, but lack responsiveness to IL-10. By ∼12 wk of age, the majority of mutant mice raised in a conventional facility developed a chronic colitis and splenomegaly. Thus, CRFB4 mutant mice recapitulate the phenotype of IL-10–deficient mice. These findings suggest that CRF2-4 is essential for IL-10–mediated effects and is a subunit of the IL-10 receptor.

Identification of the Zebrafish IFN Receptor: Implications for the Origin of the Vertebrate IFN System

“…It is difficult to assign a mammalian ortholog to either of these receptors, but until now, all tested CRFBs appear to be dispensable for development in mice (6,43). Interestingly, however, in some mammals, type I IFNs have a function in embryo-maternal communication (44).…”

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

“…19,[27][28][29] The IL-10R1 chain plays a dominant role in mediating high-affinity ligandbinding and signal transduction, whereas the IL-10R2 subunit is thought to be required for signaling. 30,31 Interaction of IL-10 with the IL-10R complex stabilizes dimerization of both IL-10R subunits, activates phosphorylation of the receptor-associated Janus tyrosine kinases, Jak1 and Tyk2 32,33 and induces mainly STAT3-mediated signal transduction. [34][35][36] Our group recently identified two novel SNP of the IL-10R1, 37 one of which (G330R, SNP4) affects IL-10-mediated inhibition of TNFa production in human monocytes.…”

IL-10 gene therapy prevents TNBS-induced colitis

“…1,2 The activity of IL-10 in counter regulating mucosal inflammation is likely to be multifactorial. IL-10 is a potent down regulator of IL-12 production and thus acts at the level of Th1 cell induction.…”