title: IL-1 signal affects both protection and pathogenesis of virus-induced chronic CNS demyelinating disease.
abstract: BACKGROUND
  Theiler's virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS). IL-1 plays an important role in the pathogenesis of both the autoimmune disease model (EAE) and this viral model for MS. However, IL-1 is known to play an important protective role against certain viral infections. Therefore, it is unclear whether IL-1-mediated signaling plays a protective or pathogenic role in the development of TMEV-induced demyelinating disease.
  
  
  METHODS
  Female C57BL/6 mice and B6.129S7-Il1r1tm1Imx/J mice (IL-1R KO) were infected with Theiler's murine encephalomyelitis virus (1 x 106 PFU). Differences in the development of demyelinating disease and changes in the histopathology were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected mice were analyzed using quantitative PCR, ELISA, and flow cytometry.
  
  
  RESULTS
  Administration of IL-1β, thereby rending resistant B6 mice susceptible to TMEV-induced demyelinating disease, induced a high level of Th17 response. Interestingly, infection of TMEV into IL-1R-deficient resistant C57BL/6 (B6) mice also induced TMEV-induced demyelinating disease. High viral persistence was found in the late stage of viral infection in IL-1R-deficient mice, although there were few differences in the initial anti-viral immune responses and viral persistent levels between the WT B6 and IL-1R-deficiecent mice. The initial type I IFN responses and the expression of PDL-1 and Tim-3 were higher in the CNS of TMEV-infected IL-1R-deficient mice, leading to deficiencies in T cell function that permit viral persistence.
  
  
  CONCLUSIONS
  These results suggest that the presence of high IL-1 level exerts the pathogenic role by elevating pathogenic Th17 responses, whereas the lack of IL-1 signals promotes viral persistence in the spinal cord due to insufficient T cell activation by elevating the production of inhibitory cytokines and regulatory molecules. Therefore, the balance of IL-1 signaling appears to be extremely important for the protection from TMEV-induced demyelinating disease, and either too much or too little signaling promotes the development of disease.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Ave, Chicago, IL 60611, USA. bskim@northwestern.edu
authors.forename: Byung S
authors.initials: BS
authors.lastname: Kim
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Jin
authors.forename: Liping
authors.initials: L
authors.lastname: Meng
authors.forename: Wanqiu
authors.initials: W
authors.lastname: Hou
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Kang
authors.forename: Hey Suk
authors.initials: HS
authors.lastname: Park
authors.forename: Chang-Sung
authors.initials: CS
authors.lastname: Koh
mesh_terms: D000818:Animals; D003711:Demyelinating Diseases / Q000209:etiology / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D005260:Female; D053583:Interleukin-1beta / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000209:etiology / Q000473:pathology / Q000821:virology; D011051:Poliomyelitis / Q000209:etiology / Q000473:pathology / Q000821:virology*; D015398:Signal Transduction / Q000276:immunology*; D017945:Theilovirus / Q000254:growth & development / Q000276:immunology
chemical_list: D053583:Interleukin-1beta