Notch3 inhibition in myelin-reactive T cells down-regulates protein kinase C theta and attenuates experimental autoimmune encephalomyelitis.
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 gamma-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 gamma-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 Ctheta, 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.
Jurynczyk
Maciej
M
Department of Neurology, Medical University of Lodz, 22 Kopcinskiego Street, Lodz, Poland.
Jurewicz
Anna
A
Raine
Cedric S
CS
Selmaj
Krzysztof
K
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D009186:Myelin Sheath / Q000276:immunology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D000074121:Protein Kinase C-theta; D012333:RNA, Messenger / Q000096:biosynthesis; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D019138:Antibodies, Blocking; D007527:Isoenzymes; C497762:Notch1 protein, mouse; C499373:Notch3 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D053829:Amyloid Precursor Protein Secretases