IFN-gamma 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 oxide.
NO and IFN-gamma 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-gamma receptor (IFNgammaR-/-), we have previously shown that IFN-gamma 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-gamma 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 IFNgammaR+/+ mice inhibit Ag-driven proliferation of IFNgammaR-/- lymphocytes, whereas IFNgammaR-/- 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-gamma 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.
Willenborg
D O
DO
Neurosciences Research Unit, Canberra Hospital, Woden, Australian Capital Territory, Australia. david.willenborg@anu.edu.au
Fordham
S A
SA
Staykova
M A
MA
Ramshaw
I A
IA
Cowden
W B
WB
D000595:Amino Acid Sequence; D000818:Animals; D001202:Ascitic Fluid / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors / Q000276:immunology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D011828:Radiation Chimera / Q000276:immunology; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000637:transplantation; D000096743:Interferon gamma Receptor
D004791:Enzyme Inhibitors; D007371:Interferon-gamma; D016753:Interleukin-10; D015847:Interleukin-4; D018992:Myelin-Associated Glycoprotein; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C496317:Nos2 protein, mouse