IL-12/IFN-γ/NO axis plays critical role in development of Th1-mediated experimental autoimmune encephalomyelitis

Abstract

The importance of the IL-12/IFN-γ/nitric oxide (NO) axis in the pathogenesis of autoimmune diseases remains controversial. In parallel experiments, we explored the role of the IL-12/IFN-γ/NO axis in the development of MOG 35-55-induced experimental autoimmune encephalomyelitis (EAE) in mice lacking IL-12, IFN-γ receptor (IFN-γR) and inducible nitric oxide synthase (NOS2), respectively. In comparison with wide-type control mice, IL-12 −/−, IFN-γR −/− and NOS2 −/− mice displayed more severe clinical signs of EAE both in remission and at subsequent relapse. Given the relatively low IFN-γ production in IL-12 −/− mice and the lack of IFN-γ/IFN-γR signaling pathway in IFN-γR −/− mice, IL-12 −/−, IFN-γR −/− and NOS2 −/− mice with EAE exhibited low NO production. This correlated negatively with MOG 35-55-induced T cell proliferation. Both ED1-positive macrophages and CD4-positive T cells were increased in spinal cords from IL-12 −/−, IFN-γR −/− and NOS2 −/− compared to control mice. In vitro experiments demonstrate that spleen mononuclear cells from IL-12 −/−, IFN-γR −/− and NOS2 −/− mice with EAE present stronger migration capacity when compared to control mice. These results reveal that the IL-12/IFN-γ/NO axis plays a critical role in the development of MOG 35-55-induced EAE, possibly over failing NO production.