IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System Journal Articles uri icon

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abstract

  • AbstractInflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-γ, a cytokine not normally expressed in the CNS. To investigate the role of IFN-γ in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-γ (AdIFNγ) to IFN-γ-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-γ that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-γ induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-γR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-γ-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-γ vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-γ induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-γ-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.

authors

  • Millward, Jason M
  • Caruso, Maria
  • Campbell, Iain L
  • Gauldie, Jack
  • Owens, Trevor

publication date

  • June 15, 2007