title: Dendritic cell-derived nitric oxide is involved in IL-4-induced suppression of experimental allergic encephalomyelitis (EAE) in Lewis rats.
abstract: Cytokines play a crucial role in initiating and perpetuating EAE, an animal model of multiple sclerosis (MS). A low dose of IL-4, administered by the nasal route over 5 days (100 ng/rat per day) prior to immunization, improved clinical scores of EAE induced in Lewis rats with myelin basic protein (MBP) peptide 68-86 (MBP 68-86). We examined whether dendritic cells (DC) may have contributed to the amelioration of the disease process. These professional antigen-presenting cells (APC) not only activate T cells, but also tolerize T cells to antigens, thereby minimizing autoimmune reactions. We found that IL-4 administration enhanced proliferation of DC. In comparison with DC of PBS-treated rats, DC from IL-4-treated rats secreted high levels of interferon-gamma (IFN-gamma) and IL-10. Nitric oxide (NO) production by DC was also strongly augmented in IL-4-treated rats. In vitro studies showed that IL-4 stimulated DC expansion and that IFN-gamma enhanced NO production by DC. DC-derived NO promoted apoptosis of autoreactive T cells. These results indicate that nasal administration of IL-4 promotes activation of DC and induces production of IFN-gamma and IL-10 by DC. IL-10 suppresses antigen presentation by DC, while IFN-gamma induces NO production by DC which leads to apoptosis in autoreactive T cells. Such a DC-derived negative feedback loop might contribute to the clinical improvement observed in EAE.
authors.affiliation: Division of Neurology, Unit of Experimental Neurobiology and Neuroimmunology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: P H
authors.initials: PH
authors.lastname: Van Der Meide
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: B
authors.initials: B
authors.lastname: Wahren
authors.forename: H
authors.initials: H
authors.lastname: Link
authors.forename: B
authors.initials: B
authors.lastname: Xiao
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects; D004676:Myelin Basic Protein / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology
chemical_list: D004676:Myelin Basic Protein; D016753:Interleukin-10; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma