title: IL-Y, a synthetic member of the IL-12 cytokine family, suppresses the development of type 1 diabetes in NOD mice.
abstract: 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 α and β 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-27Rα in splenocytes. Adenoviral-mediated, intratumoral delivery of scIL-Y increased tumor growth in contrast to the anti-tumor 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-γ. 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.
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Rafael R
authors.initials: RR
authors.lastname: Flores
authors.affiliation: Departments of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Eun
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Liqiao
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Chenjie
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Departments of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.|Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gambotto
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.|Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD
chemical_list: D018664:Interleukin-12
keywords: Adenovirus; Interleukin-12; NOD mice; Regulatory T cells; Type 1 diabetes