IL-Y, a synthetic member of the IL-12 cytokine family, suppresses the development of type 1 diabetes in NOD mice

The IL-12 family of heterodimeric cytokines, consisting of IL-12, IL-23, IL-27, and IL-35, has important roles in regulating the immune response. IL-12 family members are comprised of a heterodimer consisting of alpha and beta chains: IL-12 (p40 and p35), IL-23 (p40 and p19), IL-27 (Ebi3 and p28), and IL-35 (Ebi3 and p35). Given the combinatorial nature of the IL-12 family, we generated adenoviral vectors expressing two putative IL-12 family members not yet found naturally, termed IL-X (Ebi3 and p19) and IL-Y (p40 and p28), as single-chain molecules. Single chain IL-Y (scIL-Y), but not scIL-X, was able to stimulate significantly a unique cytokine/ chemokine expression profile as well as activate STAT3 in mice, in part, through a pathway involving IL-27R alpha in splenocytes. Adenoviral-mediated, intratumoral delivery of scIL-Y increased tumor growth in contrast to the antitumor effects of scIL-12 and scIL-23. Similarly, treatment of prediabetic NOD mice by intravenous injection of Ad. scIL-Y prevented the onset of hyperglycemia. Analysis of cells from Ad. scIL-Y-treated NOD mice demonstrated that scIL-Y reduced expression of inflammatory mediators such as IFN-gamma. Our data demonstrate that a novel, synthetic member of the IL-12 family, termed IL-Y, confers unique immunosuppressive effects in two different disease models and thus could have therapeutic applications.