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2-Deficient Mice: IL-12 Responsiveness Is Not Required in the Pathogenesis of Inflammatory Demyelination in the Central Nervous System1
Departments of
*
Neurology,
Neurosurgery, and
Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
IL-12 is thought to be involved in the susceptibility to experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. IL-12 signals through a heterodimeric receptor (IL-12R
1/IL-12R2), whose 2-chain is up-regulated on activated, autoreactive Th1 cells. Contrary to the expectation that the absence of IL-12R2 would protect from EAE, we found that IL-12R2-deficient mice developed earlier and more severe disease, with extensive demyelination and CNS inflammation. The inflammatory cells were mainly comprised of CD4+ T cells, monocyte/macrophages, and dendritic cells. Compared to wild-type mice, IL-12R2-deficient mice exhibited significantly increased autoantigen-induced proliferative response and increased production of TNF-
, GM-CSF, IL-17, IL-18/IL-18R, and NO. In addition, we found significantly increased levels of IL-23p19 mRNA expression in spleen cells from immunized IL-12R2-/- mice compared with wild-type mice. These findings indicate that IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS, and that, in the absence of IL-12R2, increased IL-23 and other inflammatory molecules may be responsible for increased severity of EAE.
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