A soluble form of IL-27Rα is a natural IL-27 antagonist

IL-27 is a cytokine of the IL-12 family that plays a key role in the regulation of inflammatory and T cell responses. Its receptor is composed of IL-27Rα and gp130 and activates the STAT pathway. We show in this study, using an ELISA that we developed, that a naturally occurring soluble form of IL-27Rα (sIL-27Rα) is produced by human activated CD4(+) and CD8(+) T cells, B cells, myeloid cells, and various cell lines. sIL-27Rα is present at a mean concentration of 10,344 ± 1,274 pg/ml in the sera from healthy individuals. Biochemical studies showed that sIL-27Rα is released as two N-glycosylated variants of ∼ 90 and ∼ 70 kDa. In IL-27Rα-transfected COS7 cells, primary cells, and cell lines, production of sIL-27Rα is inhibited by the metalloprotease inhibitors GM6001 and TAPI-0. Importantly, natural sIL-27Rα binds rIL-27, inhibits IL-27 binding to its cell surface receptor, and is a potent inhibitor of IL-27 signaling, as shown by its ability to specifically block IL-27-mediated STAT activation, at low molar excess over IL-27. Also, we found that serum levels of sIL-27Rα were elevated in patients with Crohn's disease, a Th1-mediated disease. These findings suggest that sIL-27Rα may play important immunoregulatory functions under normal and pathological conditions.