MOG(35-55) i.v suppresses experimental autoimmune encephalomyelitis partially through modulation of Th17 and JAK/STAT pathways.
Intravenous (i.v.) administration of encephalitogenic peptide can effectively prevent experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis; however, the underlying cellular and molecular mechanisms are not fully understood. In this study, we induced i.v. tolerance to EAE by administration of MOG(35-55) peptide and determined the effect of this approach on intracellular signaling pathways of the IL-23/IL-17 system, which is essential for the pathogenesis of MS/EAE. In tolerized mice, phosphorylation of JAK/STAT-1, -4, ERK1/2 and NF-kappaBp65 were significantly reduced in splenocytes and the central nervous system. MOG i.v. treatment led to significantly lower production of IL-17, and administration of exogenous IL-17 slightly broke immune tolerance, which was associated with reduced activation of STAT4 and NF-kappaB. Suppressed phosphorylation of these pathway molecules was primarily evident in CD11b(+) and small numbers of CD4(+), CD8(+) and CD11c(+) cells. More importantly, adoptive transfer of CD11b(+) splenocytes of tolerized mice effectively delayed onset and reduced clinical severity of actively induced EAE. This study correlates MOG i.v. tolerance with modulation of Jak/STAT signaling pathways and investigates novel therapeutic avenues for the treatment of EAE/MS.
Jiang
Zhilong
Z
Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Li
Hongmei
H
Fitzgerald
Denise C
DC
Zhang
Guang-Xian
GX
Rostami
Abdolmohamad
A
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D053612:Janus Kinases / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D006023:Glycoproteins; D020381:Interleukin-17; D053759:Interleukin-23; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B; D010446:Peptide Fragments; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases