The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties

The ability to modify responses to type I interferons (IFNs) could alter processes such as hematopoiesis and immunity, which involve endogenous IFNs and responses to exogenous IFNs. The data presented here support a significant role for a recently identified soluble isoform of the murine type I IFN receptor, mulfnar-2a, as an efficient regulator of IFN responses. The messenger RNA (mRNA) transcript encoding mulfnar-2a is generally more abundant than that encoding the transmembrane isoform, mulfnar-2c, Furthermore, the ratio of mulfnar-2a:2c transcripts varied from more than 10:1 in the liver and other organs to less than 1:1 in bone-marrow macrophages, indicating independent regulation of the 2 transcripts encoding receptor isoforms and suggesting that the soluble mulfnar-2a levels are biologically relevant in some organs. Western blot analysis showed that soluble mulfnar-2 was present at high levels in murine serum and other biologic fluids and bound type I IFN, Recombinant mulfnar-2a competitively inhibited the activity of both IFN alpha and beta in reporter assays using the L929 cell line and in antiproliferative and antiviral assays using primary cells. Surprisingly, using primary thymocytes from Ifnar-2(-/-) mice, recombinant mulfnar-2a formed a complex with IFN alpha or beta and mulfnar-1 at the cell surface and transmitted an antiproliferative signal. These data indicate potential dual actions of soluble mulfnar-2 and imply that a signal can be transduced through the Ifnar-1 chain of the receptor complex in the absence of the cytoplasmic domain of Ifnar-2, Therefore, our results suggest that soluble Ifnar-2 is an important regulator of endogenous and systemically administered type I IFN. (C) 2001 by The American Society of Hematology.