Concluding remarks

A significant down-regulation of Ets-1, c-jun, p50, Max, and p53 mRNA and a significant up-regulation of c-fos mRNA was detected between neonatal and adult SJL/J control mice. Physiologic processes during postnatal CNS development including cell differentiation and apoptosis as well as myelination might depend on the tightly controlled spatio-temporal expression of these IEGs. In addition, the IEG expression pattern in TME pointed to specific functions of these transcription factors in this animal model for different demyelinating diseases such as CDV and MS.

The early phase of TME is characterized by a moderate upregulation of Ets-1, c-jun, c-fos, p50, and p65 in susceptible SJL/J mice probably driving a pro-inflammatory cascade. These events seem to be prevented in resistant C57BL/6 mice by the lack of increased c-jun and p65 mRNA transcript levels. In addition, a strong and fast anti-viral IFN-γ response of this mouse strain might be caused by a strong upregulation of

Discussion 133

the up-stream transcription factors Ets-1 and p50 at 1 hpi. The late phase of TME is characterized by an increase of all investigated IEGs in SJL/J in contrast to C57BL/6 mice. The interaction of Ets-1 and JUN/JUN homodimers in intralesional astrocytes might trigger a continuous release of pro-inflammatory cytokines and MMPs in SJL/J mice thereby promoting lesion progression and inhibiting axonal growth and remyelination (BASSUK and LEIDEN, 1995; LOGAN et al., 1996). In addition, critical immune cell functions implicated in myelin destruction might be related to the spatio-temporal cell type specific expression of Ets-1, AP-1, and NF-κB proteins (GERHAUSER et al., 2005; ROSENBERG, 2002; ULRICH et al., 2005; ULRICH et al., 2006; WESTERMARCK and KÄHÄRI, 1999). However, further studies are needed to elucidate the interactions of the investigated and other transcription factors in promoter regions in order to create potential targets for future therapeutical intervention.

Summary 135

Chapter 6

Summary

136 Summary

Ingo Gerhauser – The role of “Immediate Immediate Early Genes” in the central nervous system of susceptible and resistant mouse strains during Theiler´s murine encephalomyelitis

Theiler’s murine encephalomyelitis (TME) represents an important virus-induced mouse model to study demyelinating disesases including canine distemper virus and multiple sclerosis. The persistence of the TME virus (TMEV) in the spinal cord of susceptible SJL/J mice triggers the release of different cytokines and matrix-metalloproteinases (MMPs) that participate in the demyelination process. In contrast, a strong antiviral immune response prevents virus persistence and demyelination in resistant C57BL/6 mice. Gene products of immediate early genes (IEGs) including Ets-1, c-jun, c-fos, NF-κB, Max, and p53 are interacting transcription factors binding to specific sites in promoter regions of inducible and constitutively expressed genes.

Thereby, they control transcription of downstream targets, like cytokines, MMPs, and pro- and anti-apoptotic genes. MMPs are known to play an important role in development, plasticity, response to injury, and repair of the central nervous system (CNS). The Ets-1 transcription factor is also involved in the maturation and activation of different NK-, T-, and B cell lineages. However, specific expression patterns of these transcription factors in control animals and TME susceptible and resistant mouse strains as well as their relationship to demyelination remain to be determined.

A real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical investigation was performed to study age-dependent mRNA expression levels and protein distribution patterns of all above mentioned IEGs in cerebrum, cerebellum, and spinal cord of non-infected SJL/J mice between postnatal weeks 1 and 40. In addition, the mRNA expression of Ets-1, c-fos, c-jun, and NF-κB (p50, p65), as well as TMEV, TNF-α, and IFN-γ genes was quantified in the spinal cord of TMEV (BeAn strain)-infected SJL/J and C57BL/6 mice until 196 days post infection (dpi) using RT-qPCR. TMEV-infected spinal cords were also examined for Ets-1, c-fos, c-jun, and p50 expression applying immunohistochemistry.

The inflammatory process of TME was characterized by quantifying perivascular and intralesional CD3⁺, CD4⁺, CD8⁺, CD45R⁺, and Mac-1⁺ cells.

Summary 137

An age-dependent downregulation of Ets-1, c-jun, p50, Max, and p53 mRNA, and an upregulation of c-fos mRNA was noticed in cerebrum, cerebellum, and spinal cord of non-infected SJL/J mice. Downregulations of Ets-1 and p53 were most prominent between week 1 and 3. One week old mice were strongly immunopositive for Ets-1, c-jun, and Max in cerebral cortex, medulla oblongata, and gray matter of the spinal cord. A high staining intensity was detected in the developing granule cell layer of the cerebellum for c-jun and Ets-1, and in the Purkinje cell layer of the cerebellum for Max. Surprisingly, in contrast to the downregulation of most mRNAs in adult mice, immunohistochemistry demonstrated minor upregulations of all IEG proteins in restricted parts of the CNS.

TMEV-infected mice demonstrated a mouse-strain specific expression pattern for all investigated IEGs. Susceptible SJL/J mice showed an upregulation of AP-1 and NF-κB mRNA transcripts in the early (0-7 dpi) and late phase (28-196 dpi) of TME, whereas in resistant C57BL/6 mice these IEGs were only upregulated until 4 dpi.

Furthermore, a stronger upregulation of Ets-1 mRNA transcripts was found until 7 dpi in C57BL/6 compared to SJL/J mice. In the latter, Ets-1 was low in the early phase and moderately increased in the late phase of TME. Though an increased TNF-α and IFN-γ expression after TMEV-infection was found in both investigated mouse strains in the early phase of TME, the IFN-γ response was observed more rapidly in C57BL/6 mice. Resistant mice cleared the virus from the spinal cord. In contrast, SJL/J mice developed a heavy viral burden, strongly increased cytokine mRNA transcript levels, extensive white matter lesions dominated by CD4⁺ T cells and macrophages, and progressive demyelination in the late phase of TME. The majority of intralesional astrocytes showed an immunoreaction for Ets-1, c-jun, and p50.

Although most mononuclear immune cells demonstrated an immunostaining for Ets-1, barely half of these cells was immunopositive for p50.

The results indicated a cell-type specific IEG expression pattern, which was influenced by the genetic background of the investigated mouse strains, as well as physiological and pathological stimuli. A prominent role in CNS development especially the cerebellum was found for Ets-1, c-jun, and Max by comparing their expression between neonatal and adult SJL/J mice. In addition, the expression of

138 Summary

AP-1 and NF-κB proteins in resident glial cells after TMEV-infection was followed by a strong downstream TNF-α production. This might account for disease development in susceptible SJL/J mice. Virus persistence and lesion development in resistant C57BL/6 mice seemed to be prevented by the strong induction of Ets-1 and IFN-γ in the early phase of TME. In the contrary, the formation of JUN/JUN homodimers as well as a delayed and moderate Ets-1 activation in intralesional astrocytes might contribute to the sustained release of pro-inflammatory cytokines, thereby promoting disease progression.

Zusammenfassung 139

Chapter 7

Zusammenfassung

140 Zusammenfassung

Ingo Gerhauser – Die Rolle von “Immediate Immediate Early Genes” im zentralen Nervensystem von empfänglichen und resistenten Mäusestämmen im Verlauf der murinen Theilervirus-Enzephalomyelitis

Die murine Theilervirus-Enzephalomyelitis („Theiler’s murine encephalomyelitis“;

TME) stellt ein wichtiges, virusinduziertes Tiermodell für demyelinisierende Erkrankungen wie die kanine Staupe oder die multiple Sklerose des Menschen dar.

Die Persistenz des Theilervirus („Theiler’s murine encephalomyelitis virus“; TMEV) im Rückenmark von empfänglichen SJL/J-Mäusen löst die Freisetzung von verschiedenen Zytokinen und Matrix-Metalloproteinasen (MMPs) aus, die eine Rolle im Entmarkungsprozess spielen. Im Gegensatz hierzu verhindert eine starke antivirale Immunantwort in resistenten C57BL/6-Mäusen die Viruspersistenz und die Demyelinisierung. Genprodukte von „immediate early genes” (IEGs), wie zum Beispiel Ets-1, c-jun, c-fos, NF-κB, Max und p53, sind interagierende Transkriptionsfaktoren, die an spezifische Stellen in der Promoterregion von induzierbaren und konstitutiv exprimierten Genen binden. Dadurch kontrollieren sie die Transkription von nachgelagerten Zielgenen, unter anderem Zytokinen, MMPs, und pro- und anti-apoptotischen Genen. MMPs sind an der Entwicklung, der Plastizität und der Reaktion auf Gewebsschädigungen inklusive der Wiederherstellung vorherbestandener Gewebsstrukturen des zentralen Nervensystems (ZNS) beteiligt. Der Transkriptionsfaktor Ets-1 beeinflusst auch die Reifung und Aktivierung von natürlichen Killerzellen, sowie T- und B-Lymphozyten.

Allerdings fehlen Studien über die spezifischen Expressionsmuster dieser Transkriptionsfaktoren in Kontrolltieren, sowie empfänglichen und resistenten Mäusestämmen im Verlauf der TME und ihre Verbindung zur Entmarkung.

Eine quantitative RT-PCR (RT-qPCR) und eine immunhistologische Untersuchung wurden benutzt, um die altersabhängige mRNA- und Protein-Expression der oben genannten IEGs im Großhirn, Kleinhirn und Rückenmark von nicht-infizierten SJL/J-Mäusen zwischen der ersten und der vierzigsten Lebenswoche zu studieren.

Außerdem wurde die mRNA-Expression der Ets-1, c-fos, c-jun, NF-κB (p50, p65), TMEV, TNF-α und IFN-γ Gene im Rückenmark von TMEV (BeAn-Stamm)-infizierten

Zusammenfassung 141

SJL/J- und C57BL/6-Mäusen bis zum 196. Tag post infectionem (Tpi) mittels RT-qPCR quantifiziert. Die Ets-1-, c-fos-, c-jun- und p50-Expression in TMEV-infiziertem Rückenmark wurde ebenfalls mit immunhistologischen Methoden untersucht. Zur Charakterisierung des Entzündungsprozesses im Verlauf der TME wurden die perivaskulären und intraläsionalen CD3-, CD4-, CD8-, CD45R- und Mac-1-positiven Zellen ausgezählt.

Ein alterabängiger Abfall an Ets-1, c-jun, p50, Max und p53 mRNA, sowie ein Anstieg an c-fos mRNA wurde im Großhirn, Kleinhirn und Rückenmark von nicht infizierten SJL/J-Mäusen festgestellt. Dieser Abfall wurde besonders bei Ets-1 und p53 zwischen der ersten und dritten Lebenswoche beobachtet. Mäuse zeigten im Alter von einer Woche eine starke Immunreaktion für Ets-1, c-jun, und Max im zerebralen Kortex, verlängertem Rückenmark und der grauen Substanz des Rückenmarks. Die sich entwickelnde Granularzellschicht des Kleinhirns wies eine ausgeprägte Immunreaktion für c-jun und Ets-1 auf. In der Purkinjezellschicht des Kleinhirns fand sich eine starke Reaktion für Max. Überraschenderweise wurde neben dem altersabhängigen Abfall der meisten mRNA Transkripte lokal begrenzt mittels Immunhistologie eine verstärkte Expression der IEG-Proteine im ZNS von adulten Mäusen festgestellt.

Bei TMEV-infizierten Mäusen wurde ein mausstammspezifisches Expressionsmuster aller untersuchten IEGs beobachtet. Empfängliche SJL/J-Mäuse wiesen einen Anstieg an AP-1 und NF-κB mRNA Transkripten in der Früh- (0-7 Tpi) und Spätphase (28-196 Tpi) der TME auf, während bei resistenten C57BL/6-Mäusen diese IEGs nur bis zum 4. Tpi aufreguliert waren. Außerdem wurde bis zum 7. Tpi ein stärkerer Anstieg an Ets-1 mRNA Transkripten bei C57BL/6-im Vergleich zu SJL/J-Mäusen festgestellt. Bei diesen empfänglichen SJL/J-Mäusen war Ets-1 nur geringgradig in der Frühphase und mittelgradig in der Spätphase der TME aufreguliert. Obwohl TNF-α and IFN-γ bei beiden untersuchten Mäusestämmen nach einer TMEV-Infektion in der Frühphase der TME aufreguliert waren, zeigten die C57BL/6-Mäuse einen schnelleren Anstieg der IFN-γ-Expression. Während diese resistenten Mäuse das Virus aus dem Rückenmark eliminierten, zeigten die SJL/L-Mäuse in der Spätphase der TME einen hohen Virusgehalt, ein stark erhöhtes Niveau an

Zytokin-mRNA-142 Zusammenfassung

Transkripten, ausgedehnte Läsionen in der weißen Substanz mit zahlreichen CD4-positiven T-Zellen und Makrophagen, sowie eine fortschreitende Demyelinisierung.

Intraläsionale Astrozyten wiesen mehrheitlich eine positive Immunreaktion für Ets-1, c-jun und p50 auf. Obwohl die meisten mononukleären Immunzellen positiv für Ets-1 waren, zeigte nur knapp die Hälfte eine Immunreaktion für p50.

Die Ergebnisse deuten auf ein zelltypspezifisches IEG-Expressionsmuster hin, welches einerseits durch den genetischen Hintergrund der untersuchten Mäusestämme als auch durch physiologische und pathologische Stimuli beeinflusst wird. Eine herausragende Rolle bei der ZNS- insbesondere der Kleinhirn-Entwicklung konnte für Ets-1, c-jun und Max durch den Vergleich ihrer Expression in neonatalen und adulten SJL/J-Mäusen nachgewiesen werden. Des Weiteren könnte die AP-1- und NF-κB-Proteinexpression in ortsständigen Gliazellen nach einer TMEV-Infektion mit der nachfolgenden TNF-α-Produktion und ebenfalls mit der Entstehung der Erkrankung im Zusammenhang stehen. Die Viruspersistenz und Entwicklung der Läsionen in resistenten C57BL/6-Mäusen wird anscheinend durch die starke Induktion von Ets-1 und IFN-γ in der Frühphase der TME verhindert. Demgegenüber scheinen intraläsionale Astrozyten über eine Bildung von JUN/JUN-Homodimeren sowie eine verzögerte und mäßige Aktivierung von Ets-1 an einer ständigen Freisetzung von pro-inflammatorischen Zytokinen und dadurch an einem Fortschreiten der Erkrankung beteiligt zu sein.

References 143

Chapter 8

References

144 References

ABRAHAM, W. C., S. E. MASON, J. DEMMER, J. M. WILLIAMS, C. L. RICHARDSON, W. P. TATE, P. A. LAWLOR, and M. DRAGUNOW (1993): Correlations between immediate early gene induction and the persistence of long-term potentiation. Neuroscience 56, 717–727

ACHIRON, A. and Y. BARAK (2003): Cognitive impairment in probable multiple sclerosis. J. Neurol.

Neurosurg. Psychiatry. 74, 443-446

ALLDINGER, S., W. BAUMGÄRTNER, P. VAN MOLL, and C. ÖRVELL (1993a): In vivo and in vitro expression of canine distemper viral proteins in dogs and non-domestic carnivores. Arch. Virol.

132, 421-428

ALLDINGER, S., W. BAUMGÄRTNER, and C.ÖRVELL (1993b): Restricted expression of viral surface proteins in canine distemper encephalitis. Acta Neuropathol. 85, 635-645

ALLDINGER, S., A. WÜNSCHMANN, W. BAUMGÄRTNER, C. VOSS, and E. KREMMER (1996): Up-regulation of major histocompatibility complex class II antigen expression in the central nervous system of dogs with spontaneous canine distemper virus encephalitis. Acta Neuropathol. 92, 273-280

ALLDINGER, S., S. FONFARA, E. KREMMER, and W. BAUMGÄRTNER (2000): Up-regulation of the hyaluronate receptor CD44 in canine distemper demyelinated plaques. Acta Neuropathol. 99, 138-146

ALLDINGER, S. and C. J. R. WELSH (2003): Expression of matrix-metalloproteinases and their inhibitors in Theiler’s murine encephalomyelitis-variation with virus strain. Acta Neuropathol. 106, 401

ALLDINGER, S., S. GRÖTERS, Q. MIAO, S. FONFARA, E. KREMMER, and W. BAUMGÄRTNER (2006): Roles of an extracellular matrix (ECM) receptor and ECM processing enzymes in demyelinating canine distemper encephalitis. Dtsch. Tierärztl. Wochenschr. 113, 151-152, 154-156

AMATI, B., S. DALTON, M. W. BROOKS, T. D. LITTLEWOOD, G. I. EVAN, and H. LAND (1992):

Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max.

Nature 359, 423-426

AMEYAR, M., M. WISNIEWSKA, and J. B. WEITZMAN (2003): A role for AP-1 in apoptosis: the case for and against. Biochimie 85, 747-752

ANDREWS, H., K. WHITE, C. THOMSON, J. EDGAR, D. BATES, I. GRIFFITHS, D. TURNBULL, and P. NICHOLS (2006): Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse. J. Neurosci. Res. 83, 1533-1539

ANGEL, P. and M. KARIN (1991): The role of JUN, FOS and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta 10, 129-157

ANTHONY, D. C., K. M. MILLER, S. FEARN, M. J. TOWNSEND, G. OPDENAKKER, G. M. WELLS, J.

M. CLEMENTS, S. CHANDLER, A. J. GEARING, and V. H. PERRY (1998): Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS. J. Neuroimmunol. 87, 62-72

BAEUERLE, P. A., and T. HENKEL (1994): Function and activation of NF-kappa B in the immune system. Annu. Rev. Immunol. 12,141–179

BAR-OR, A., E. M. L. OLIVEIRA, D. E. ANDERSON, and D. A. HAFLER (1999): Molecular pathogenesis of multiple sclerosis. J. Neuroimmunol. 100, 252-259

BAR-OR, A., R. K. NUTTALL, M. DUDDY, A. ALTER, H. J. KIM, I. IFERGAN, C. J. PENNINGTON, P.

BOURGOIN, D. R. EDWARDS, and V. W. YONG (2003): Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 126, 2738-2749

BARTON, K., N. MUTHUSAMY, C. FISCHER, C. N. TING, T. L. WALUNAS, L. L. LANIER, and J. M.

LEIDEN (1998): The Ets-1 transcription factor is required for the development of natural killer cells in mice. Immunity 9, 555-563

BASSUK, A. G. and J. M. LEIDEN (1995): A direct physical association between ETS and AP-1 transcription factors in normal human T cells. Immunity 3, 223-237

BASSUK, A. G. and J. M. LEIDEN (1997): The role of ETS transcription factors in the development and function of the mammalian immune system. Adv. Immunol. 64, 65-104

BASSUK, A. G., R. T. ANANDAPPA, and J. M. LEIDEN (1997): Physical interactions between ETS and NF-κB/NFAT proteins play an important role in their cooperative activation of the human immunodeficiency virus enhancer in T cells. J. Virol. 71, 3563-3573

References 145

BAUMGÄRTNER ,W., C. ÖRVELL, and M. REINACHER (1989): Naturally occurring canine distemper virus encephalitis: distribution and expression of viral polypeptides in nervous tissues. Acta Neuropathol. 78, 504-512

BAUMGÄRTNER, W., S. ALLDINGER, A. BEINEKE, S. GRÖTERS, C. HERDEN, U. KAIM, G.

MÜLLER, F. SEELIGER, P. VAN MOLL, and P. WOHLSEIN (2003): Canine distemper virus-an agent looking for new hosts. Dtsch. Tierärztl. Wochenschr. 110, 137-142

BAUMGÄRTNER, W. and S. ALLDINGER (2005): The pathogenesis of canine distemper virus induced demyelination: a biphasic process. In: Experimental models of multiple sclerosis. LAVI, E.

and C. S. CONSTANTINESCU (Eds.), Springer, Berlin, pp. 873-887

BEGOLKA, W. S., C. L. VANDERLUGT, S. M. RAHBE, and S. D. MILLER (1998): Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J. Immunol. 161, 4437-4446

BEHRENS, A., M. SIBILIA, and E. F. WAGNER (1999): Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat. Genet. 21, 326-329

BENNETT, M., K. MACDONALD, S. W. CHAN, J. P. LUZIO, R. SIMARI, and P. WEISSENBERG (1998): Cell surface trafficking of FAS: a rapid mechanism of p53-mediated apoptosis. Science 282, 290-293

BHAT, N. K., C. B. THOMPSON, T. LINDSTEN, C. H. JUNE, S. FUJIWARA, S. KOIZUMI, R. J.

FISHER, and T. S. PAPAS (1990): Reciprocal expression of human ETS1 and ETS2 genes during T-cell activation: regulatory role for the protooncogene ETS1. Proc. Natl. Acad. Sci. 87, 3723-3727

BLACKWOOD, E. M. and R. N. EISENMAN (1991): Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 251, 1211-1217

BLACKWOOD, E. M., L. KRETZNER, and R. N. EISENMAN (1992): Myc and Max function as a nucleoprotein complex. Curr. Opin. Genet. Dev. 2, 227-235

BONIZZI, G. and M. KARIN (2004): The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends. Immunol. 25, 280–288

BORIES, J.-D., D. M. WILLERFORD, D. GRÉVIN, L. DAVIDSON, A. CAMUS, P. MARTIN, D.

STÉHELIN, and F. W. ALT (1995): Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene. Nature 377, 635-638

BRAHIC, M., J.-F.BUREAU, and T. MICHIELS (2005): The Genetics of the persistent infection and demyelinating disease caused by Theiler’s Virus. Annu. Rev. Microbiol. 59, 279-298

BREW, K., D. DINAKARPANDIAN, and H. NAGASE (2000): Tissue inhibitors of metalloproteinases:

evolution, structure and function. Biochim. Biophys. Acta 1477, 267-283

BRIVANLOU, A. H. and J. E. DARNELL JR. (2002): Signal transduction and the control of gene expression. Science 295, 813-818

BRÜCK, W., N. SOMMERMEIER, M. BERGMANN, U. ZETTL, H. H. GOEBEL, H. A.

KRETZSCHMAR, and H. LASSMANN (1996): Macrophages in multiple sclerosis. Immunobiology 195, 588-600

CAAMAÑO, J. and C. A. HUNTER (2002): NF-κB family of transcription factors: central regulators of innate and adaptive immune functions. Clin. Microbiol. Rev. 1, 414-429

CASANOVA, E., C. GARATE, S. OVALLE, P. CALVO, and M. A. CHINCHETRU (1996): Identification of four splice variants of the mouse stress-activated protein kinase JNK/SAPK alpha-isoform.

Neuroreport 7, 1320-1324

CAUBET, J.-F. (1989): c-fos proto-oncogene expression in the nervous system during mouse development. Mol. Cell. Biol. 9, 2269-2272

CEPOK, S., D. ZHOU, R. SRIVASTAVA, S. NESSLER, S. STEI, K. BUSSOW, N. SOMMER, and B.

HEMMER (2005): Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J. Clin. Invest. 115, 1352-1360

CHAISUKSUNT, V., G. CAMPBELL, Y. ZHANG, M. SCHACHNER, A. R. LIEBERMAN, and P. N.

ANDERSON (2003): Expression of regeneration-related molecules in injured and regenerating striatal and nigral neurons. J. Neurocytol. 32, 161–183

CHAKRABORTI, S., M. MANDAL, S. DAS, A. MANDAL, and T. CHAKRABORTI (2003): Regulation of matrix metalloproteinases: an overview. Mol. Cell. Biochem. 253, 269-285

146 References

CHANG, J. R., E. ZACZYNSKA, D. KATSETOS, C. D. PLATSOUCAS, and E. L. OLESZAK (2000):

Differential expression of TGF-β, Il-2, and other cytokines in the CNS of Theiler´s murine encephalomyelitis virus-infected susceptible and resistant strains of mice. Virology 278, 346-360 CHEN, H. H., W. P. KONG, L. ZHANG, P. L. WARD, and R. P. ROOS (1995): A picornaviral protein

synthesized out of frame with the polyprotein plays a key role in a virus-induced immune-mediated demyelinating disease. Nat. Med. 1, 927-931

CHEN, R. W., P. A. SAUNDERS, H. WEI, Z. LI, P. SETH, and D. M. CHUANG (1999): Involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and p53 in neuronal apoptosis: evidence that GAPDH is upregulated by p53. J. Neurosci. 19, 9654-9662

CHEN, L.F. and W. C. GREENE (2004): Shaping the nuclear action of NF-kappaB. Nat. Rev. Mol.

Cell. Biol. 5, 392–401

CHEN, Z. J. (2005): Ubiquitin signalling in the NF-kappaB pathway. Nat. Cell. Biol. 7, 758–765 CHEN, L.F., S. A. WILLIAMS, Y. MU, H. NAKANO, J. M. DUERR, L. BUCKBINDER, and W. C.

GREENE (2005): NF-kappaB RelA phosphorylation regulates RelA acetylation. Mol. Cell. Biol. 25, 7966–7975

CHIARUGI, A (2002): Inhibitors of poly (ADP-ribose) polymerase-1 suppress transcriptional activation in lymphocytes and ameliorates autoimmune encephalomyelitis in rats. Br. J. Pharmacol. 137, 761-770

CLEMENTS, J. L., S. A. JOHN, and L. A. GARRETT-SINHA (2006): Impaired generation of CD8⁺ thymocytes in Ets-1-deficient mice. J. Immunol. 177, 905-912

CLEMENTS, J. M., J. A. COSSINS, G. M. A. WELLS, D. J. CORKILL, K. HELFRICH, L. M. WOOD, R.

PIGOTT, G. STABLER, G. A. WARD, A. J. H. GEARING, and K. M. MILLER (1997): Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-α inhibitor. J. Neuroimmunol. 74, 85-94

CONAWAY, R. C., C. S. BROWER, and J. W. CONAWAY (2002): Emerging roles of ubiquitin in transcription regulation. Science 296, 1254-1258

CREGAN, S. P., J. G. MACLAURIN, C. G. CRAIG, G. S. ROBERTSON, D. W. NICHOLSON, D. S.

PARK, and R. S. SLACK (1999): Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J. Neurosci. 19, 7860-7869

CROXFORD, J. L., J. K. OLSON, H. A. ANGER, and S. D. MILLER (2005): Initiation and exacerbation of autoimmune demyelination of the central nervous system via virus-induced molecular mimicry:

implications for the pathogenesis of multiple sclerosis. J. Virol. 79, 8581-8590

CUZNER, M. L. and G. OPDENAKKER (1999): Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system.

J. Neuroimmunol. 94, 1-14

DAL CANTO, M. C. and S. G. RABINOWITZ (1982): Experimental models of virus-induced

DAL CANTO, M. C. and S. G. RABINOWITZ (1982): Experimental models of virus-induced

Im Dokument The role of "Immediate Early Genes" in the central nervous system of susceptible and resistant mouse strains during Theiler' s murine encephalomyelitis (Seite 152-0)