Protective effect of IFN-γ during experimental autoimmune encephalomyelitis is associated with the induction of inducible nitric oxide synthase.

Abstract

Abstract Over 2.3 million people are affected by multiple sclerosis (MS), the most common demyelinating autoimmune disease of the CNS. The relapsing-remitting form of MS is the most common initial diagnosis; however, the vast majority of patients will eventually develop secondary-progressive MS. The mechanisms that contribute to the progression of MS are largely unknown. IFN-γ, a pro-inflammatory cytokine, has long been implicated in the pathogenesis of MS and its murine model, experimental autoimmune encephalomyelitis (EAE); however, protective functions have also been demonstrated. Previous studies in our lab revealed mice lacking IFN-γ signaling developed severe and progressive EAE due to an increased presence of myelin debris and lipid peroxidation in the CNS. Recently, we identified a significant increase of inducible nitric oxide synthase (iNOS) production in the brains of WT as compared with IFN-γR−/− mice at peak of disease by qRT-PCR. iNOS is an inducible enzyme that produces nitric oxide (NO) upon activation by immunological stimuli such as IFN-γ and LPS. There are conflicting data on the role of iNOS in the pathogenesis of EAE. Our preliminary findings indicate macrophages are the primary contributors to iNOS expression during disease progression. To further explore the role of iNOS in disease progression, we are studying the underlying mechanisms, key molecules involved in this process, and the effects of treatment with iNOS inhibitors on disease course, general pathology and biochemical composition of the CNS. Our results will contribute to a better understanding of the underlying mechanisms and may lead to new treatments to prevent progression of MS.