Temporal, regional, and cell-specific changes of iNOS expression after intrastriatal microinjection of interferon gamma and bacterial lipopolysaccharide.
[en] Here we study expression of the inducible isoform of nitric oxide synthases after intrastriatal microinjection of interferon-gamma and bacterial lipopolysaccharide in the rat at different time points to detect time- and localisation-dependent changes of iNOS expression. Three different areas in the striatum and the corpus callosum were evaluated. Antibodies against the glial fibrillary acidic protein and the microglia/brain macrophage epitope ED1 were used to detect colocalization of inducible nitric oxide synthase with astrocytes or activated microglia/brain macrophages, respectively. Inducible nitric oxide synthase-positive cells occurred first in intravascular and perivascular cells at 4 h. Perivascular and parenchymal inducible nitric oxide synthase expression increased up to 24 h in the striatum, whereas in the corpus callosum inducible nitric oxide synthase expression was maximal after 16 h. Inducible nitric oxide synthase was still present in perivascular cells 7 days after immunostimulation. At all time points, inducible nitric oxide synthase was predominantly detected in ED1-positive microglia/brain. Nitrotyrosine immunohistochemistry was performed to detect NO-mediated nitration of proteins at all time points. Nitrotyrosine-positive neurons and microglial cells were detected from 24 h until 7 days after immunostimulation and were absent in controls. Detailed knowledge of the changes in the time course and cellular source of inducible nitric oxide synthase expression following brain immunostimulation provide a basis for establishing treatment strategies and windows of therapeutic intervention during neuroinflammation.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Department of Neurology, University of Bonn, Sigmund-Freud Strasse 25, 53105, Bonn, Germany. m.heneka@uni-bonn.de
Dumitrescu, Lucia; Department of Neurology, University of Bonn, 53105 Bonn, Germany
Löschmann, Peter-A.; Department of Neurology, University of Bonn, 53105 Bonn, Germany
Wüllner, Ulrich; Department of Neurology, University of Bonn, 53105 Bonn, Germany
Klockgether, Thomas; Department of Neurology, University of Bonn, 53105 Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Temporal, regional, and cell-specific changes of iNOS expression after intrastriatal microinjection of interferon gamma and bacterial lipopolysaccharide.
This study was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 400, A8). The authors wish to thank Drs D.L. Feinstein and E. Galea for fruitful discussion and critical reading of the manuscript.
Becher B., Antel J.P. Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. Glia. 18:1996;1-10.
Beckman J.S., Ye Y.Z., Anderson P.G., Chen J., Acavitti M.A., Tarpey M.M., White C.R. Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol. Chem. Hoppe Seyler. 375:1994;81-88.
Benveniste, E.N., 1995. Cytokine production. In: Ransom, B., Kettenmann, H. (eds.), Neuroglia. Oxford University Press, New York, pp. 700-713.
Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:1976;248-254.
Breder C.D., Hazuka C., Ghayur T., Klug C., Huginin M., Yasuda K., Teng M., Saper C.B. Regional induction of tumor necrosis factor α expression in the mouse brain after systemic lipopolysaccharide administration. Proc. Natl. Acad. Sci. USA. 91:1994;11393-11397.
Bredt D.S., Snyder S.H. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. USA. 87:1990;682-685.
Buttery L.D., Evans T.J., Springall D.R., Carpenter A., Cohen J., Polak J.M. Immunochemical localization of inducible nitric oxide synthase in endotoxin treated rats. Lab-Invest. 71:1994;755-764.
Calka J., Wolf G., Schmitt W. Induction of cytosolic NADPH diaphorase/nitric oxide synthasein reactive microglia/macrophages after quiniolinic acid lesions in the rat striatum: an electron and light microscopical study. Histochem. Cell Biol. 105:1996;81-89.
Chao C.C., Hu S., Sheng W.S., Bu D., Bukrinsky M.I., Peterson P.K. Cytokine stimulated astrocytes damage human neurons via a nitric oxide mechanism. Glia. 16:1996;276-284.
Choi D.W., Koh J., Peters S. Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J. Neurosci. 8:1988;185-196.
Corradin S.B., Mauel J., Donini S.D., Quattrochi E., Ricciardi-Castagnoli P. Inducible nitric oxide synthase activity of cloned murine microglial cells. Glia. 7:1993;255-262.
Dawson T.M., Dawson V.L., Snyder S.H. A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann. Neurol. 32:1992;297-311.
Dijkstra C.D., Döpp E.A., Joling P., Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 54:1985;589-599.
Ding M., St.-Pierre B.A., Parkinson J.F., Medberry P, Wong J.L., Rogers N.E., Ignarro L.J., Merrill J.E. Inducible nitric oxide synthase and nitric oxide production in human fetal astrocytes and microglia. A kinetic analysis. J. Biol. Chem. 272:1997;11327-11335.
Flaris N.A., Densmore T.L., Molleston M.C., Hickey W.F. Characterization of microglia and macrophages in the central nervous system of rats: definition of the differential expression of molecules using standard and novel monoclonal antibodies in normal CNS and in four models of parenchymal reaction. Glia. 7:1993;34-40.
Frey E.A., Miller D.S., Jahr T.G., Sundan A., Bazil V., Espevik T., Finlay B.B., Wright S.D. Soluble CD 14 participates in the responses of cells to lipopolysaccharide. J. Exp. Med. 176:1992;1665-1671.
Galea E., Feinstein D.L., Reis D.J. Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc. Natl. Acad. Sci. USA. 89:1992;10945-10949.
Galea E., Reis D.J., Fox E.S., Xu H., Feinstein D.L. CD 14 mediates endotoxin induction of nitric oxide synthase in cultured brain glial cells. J. Neuroimmunol. 64:1996;19-28.
Garcion E., Sindji L., Montero-Menei C., Andre C., Brachet P., Darcy F. Expression of inducible nitric oxide synthase during rat brain inflammation: regulation by 1,25-dihydroxyvitamin D3. Glia. 22:1998;282-294.
Graeber M.B., Streit W.J., Kiefer R., Schoen S.W., Kreutzberg G.W. New expression of myelomonocytic antigens by microglia and perivascular cells following lethal motor neuron injury. J. Neuroimmunol. 27:1990;121-132.
Guilian D., Chen J., Ingeman J.E., George J.K., Noponen M. The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J. Neurosci. 12:1989;4416-4429.
Hibbs J.B., Taintor R.R., Vavrin Z. Macrophage cytotoxicity: role for L-arginine deaminase and iminon nitrogenoxidation to nitrite. Science. 235:1987;473-476.
Heneka M.T., Löschmann P.-A., Gleichmann M., Weller M., Schulz J.B., Wüllner U., Klockgether T. Induction of nitric oxide synthase and nitric oxide mediated apoptosis in neuronal PC 12 cells after stimulation with Tumor Necrosis Factor-α/lipopolysaccharide. J. Neurochem. 71:1998;88-94.
Heneka M.T., Schmidlin A., Wiesinger H. Induction of argininosuccinate synthetase in rat brain glial cells after striatal microinjection of immunostimulants. J. Cereb. Blood Flow Metab. 19:1999;898-907.
Hu J., Van Eldik L.J. S100β induces apoptotic cell death in cultured astrocytes via a nitric oxide-dependent pathway. Biochim. Biophys. Acta. 1313:1996;239-245.
Kitamura Y., Takahashi H., Matsuoko Y., Tooyama I., Kimura H., Nomura Y., Taniguchi T. In vivo induction of inducible nitric oxide synthase by microinjection with interferon-γ and lipopolysaccharide in rat hippocampus. Glia. 18:1996;233-243.
König J.F.R., Klippel R.A. The Rat Brain: A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brainstem. 1963;Williams and Wilkins, Baltimore.
Lyons C.R., Orloff G.J., Cunningham J.M. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J. Biol. Chem. 267:1992;6370-6374.
Minc-Golomb D., Tsarfaty I., Schwartz J.P. Expression of inducible nitric oxide synthase by neurons following exposure to endotoxin and cytokine. Br. J. Pharmacol. 112:1994;720-722.
Montero-Menei C.N., Sindji L., Garcion E., Mege M., Couez D., Gamelin E., Darcy F. Early events of the inflammatory reaction induced in rat brain by lipopolysaccharide intracerebral injection: relative contribution of peripherial monocytes and activated microglia. Brain Res. 24:1996;55-66.
Murphy S., Gryzbicki P. Glial NO: normal and pathological roles. Neuroscientist. 2:1996;90-99.
Pitossi F., del Rey A., Kabiersch A., Besedovsky H. Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice. J. Neurosci. Res. 48:1997;287-298.
Schmidlin A., Wiesinger H. Argininosuccinate synthetase: localisation in astrocytes and role in the production of glial nitric oxide. Glia. 24:1998;428-436.
Simmons M.L., and. Murphy S. Induction of nitric oxide synthase in glial cells. J. Neurochem. 59:1992;897-905.
Skaper S.D., Facci L., Leon A. Inflammatory mediator stimulation of astrocytes and meningeal fibroblasts induces neuronal degeneration via the nitridergic pathway. J. Neurochem. 64:1995;266-276.
Smith M.A., Richey Harris P.L., Sayre L.M., Beckman J.S., Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J. Neurosci. 17:1997;2653-2657.
Streit W.J. Microglial cells. Ransom B., Kettenmann H. Neuroglia. 1995;85-96 Oxford University Press, New York.
Stuehr D.J., Marletta M.A. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc. Natl. Acad. Sci. USA. 82:1985;7738-7742.
Stuehr D.J., Nathan C.F. Nitric oxide, a macrophage product responsible for cytosis and respiratory inhibition in tumor target cells. J. Exp. Med. 169:1989;1543-1555.
Takeuchi A., Isobe K., Miyaishi O., Sawada M., Fan Z.-H., Nakashima I., Kiuchi K. Microglial NO induces delayed neuronal death following acute injury in the striatum. Eur. J. Neurosci. 10:1998;1613-1620.
Ulevitch R.J., Tobias P.S. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13:1995;437-457.
