Dendritic cell-derived nitric oxide is involved in IL-4-induced suppression of experimental allergic encephalomyelitis (EAE) in Lewis rats.
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.
Xu
L
L
Division of Neurology, Unit of Experimental Neurobiology and Neuroimmunology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Huang
Y
Y
Yang
J
J
Van Der Meide
P H
PH
Levi
M
M
Wahren
B
B
Link
H
H
Xiao
B
B
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
D004676:Myelin Basic Protein; D016753:Interleukin-10; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma