Chemokine expression in GKO mice (lacking interferon-gamma) with experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) considered to be an animal model for mu ltiple sclerosis (MS). The detailed mechanism that specifies accumulation o f inflammatory cells within the CNS in these conditions remains a subject o f active investigation. Chemokines including IP-10, GRO-alpha, MCP-1 are pr oduced in EAE tissues selectively by parenchymal astrocytes, but the regula tory stimuli that govern this expression remain undetermined. The unexpecte d occurrence of increased EAE susceptibility in Balb/c GKO mice (lacking IF N-gamma) offered an opportunity to examine the spectrum of chemokine expres sion during immune-mediated inflammation in the absence of a single regulat ory cytokine. We found that chemokines MCP-1 and GRO-alpha were upregulated in the CNS of mice with EAE despite the GKO genotype. IP-10, which is high ly expressed in the CNS of mice with an intact IFN-gamma gene and EAE, was strikingly absent, in vitro experiments confirmed that IFN gamma selectivel y stimulates astrocytes for IP-10 expression. These results indicate that I P-10 is dependent upon IFN-gamma for its upregulation during this model dis ease, and document directly that astrocyte expression of chemokines during EAE is governed by pro-inflammatory cytokines.