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Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase C and Attenuates Experimental Autoimmune Encephalomyelitis¹

Maciej Jurynczyk^*, Anna Jurewicz^*, Cedric S. Raine and Krzysztof Selmaj^2,*

^* Department of Neurology, Medical University of Lodz, Lodz, Poland; and Department of Pathology (Neuropathology), Albert Einstein College of Medicine, New York, NY 10461

Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4⁺ T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a -secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using -secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase C, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Polish Ministry of Science Grant N40 118 431/3980 (to K.S.); Grants NS11920, NS08952, and NMSS 1001-K-11, and the Wollowick Family Foundation (to C.S.R.).

² Address correspondence and reprint requests to Prof. Krzysztof Selmaj, Department of Neurology, Medical University of Lodz, 22 Kopcinskiego Street, 90-143 Lodz, Poland. E-mail address: kselmaj{at}afazja.am.lodz.pl

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; GSI, -secretase inhibitor; ICN, intracellular Notch; LNC, lymph node cell; PKC, protein kinase C.

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