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From the Department of Neuropharmacology,*
The Scripps
Research Institute, La Jolla, California; and the Department of
Neuropathology,
University of Freiburg,
Freiburg, Germany
Interleukin (IL)-12 and interferon (IFN)-
are implicated in the
pathogenesis of immune disorders of the central nervous system (CNS).
To define the basis for the actions of these cytokines in the
CNS, we examined the temporal and spatial regulation of key
signal transducers and activators of transcription (STATs) and
suppressors of cytokine signaling (SOCS) in the brain of transgenic
mice with astrocyte production of IL-12 or in mice with experimental
autoimmune encephalomyelitis (EAE). In healthy mice, with the
exception of STAT4 and STAT6, the
expression of a number of STAT and SOCS genes
was detectable. However, in symptomatic transgenic mice and in
EAE significant up-regulation of STAT1, STAT2,
STAT3, STAT4, IRF9, and SOCS1 and SOCS3 RNA
transcripts was observed. Although the increased expression of STAT1
RNA was widely distributed and included neurons,
astrocytes, and microglia, STAT4 and STAT3 and SOCS1
and SOCS3 RNA was primarily restricted to the infiltrating mononuclear
cell population. The level and location of the STAT1,
STAT3, and STAT4 proteins overlapped with their corresponding
RNA and additionally showed nuclear localization indicative of
activation of these molecules. Thus, in both the glial
fibrillary acidic protein-IL-12 mice and in EAE the CNS expression of
key STAT and SOCS genes that regulate IL-12
(STAT4) and IFN- (STAT1, SOCS1, and
SOCS3) receptor signaling is highly regulated and compartmentalized. We
conclude the interaction between these positive and negative signaling
circuits and their distinct cellular locations likely play a defining
role in coordinating the actions of IL-12 and IFN- during the
pathogenesis of type 1 immune responses in the CNS.
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