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Is Critical to the Control of Murine Autoimmune Encephalomyelitis and Regulates Both in the Periphery and in the Target Tissue: A Possible Role for Nitric Oxide1
*
Neurosciences Research Unit, Canberra Hospital, and
University of Sydney Canberra Clinical School, Canberra, Australian Capital Territory, Australia; and
John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
NO and IFN-
have normally been considered cytotoxic and
proinflammatory molecules, respectively, in the setting of the central
nervous system inflammatory disease autoimmune encephalomyelitis (EAE).
Using mice lacking the ligand binding chain of the IFN- receptor
(IFNR-/-), we have previously shown that IFN- is
not essential for myelin oligodendrocyte glycoprotein peptide
(MOG35–55) induced EAE expression but is in fact essential
for its down-regulation. Here we examined the downstream molecular and
cellular mechanism(s) of IFN- regulation and demonstrate that
neither IL-4 nor IL-10 appear to play a role in down-regulation nor do
various lymphoid cell populations. Cells of the macrophage lineage are
key to down-regulation as evidenced by the fact that peritoneal exudate
cells from IFNR+/+ mice inhibit Ag-driven proliferation
of IFNR-/- lymphocytes, whereas
IFNR-/- peritoneal exudate cells do not. High levels
of reactive nitrogen intermediates are detected in the former cultures
but not the latter, and the inhibition of proliferation is reversible
with an inhibitor of inducible NO synthase, indicating a key role for
NO in down-regulation. Studies with bone marrow chimeras indicate that
down-regulation occurs not only systemically but also within the target
tissue. These data suggest that IFN- down-regulates EAE by inducing
inducible NO synthase and subsequently NO production, both by
macrophages in the periphery and, by inference, microglia and
astrocytes in the target tissue.
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