Pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorates experimental autoimmune encephalomyelitis by suppressing the functions of antigen presenting cells.
Pituitary adenylate cyclase-activating polypeptide (PACAP), a 38-amino acid neuropeptide belonging to the secretin-glucagon-vasoactive intestinal peptide (VIP) family, performs a variety of functions in both the nervous and immune systems. In this study, we examined the effects of PACAP on experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. When administrated intraperitoneally every other day after immunization with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, PACAP ameliorated both the clinical and pathological manifestations of EAE Ex vivo examination revealed a significant inhibition of MOG35-55-specific Th1 response in mice treated with PACAP. In vitro analysis revealed that PACAP suppressed the production of inflammatory cytokines, including TNF-alpha, IL-1beta, and IL-12, and expression of the costimulatory factor B7-2 on macrophage and microglia, which may function as antigen presenting cells (APC) in the CNS. While PACAP suppressed the differentiation of MOG35-55-specific T cells into Th1 effectors upon restimulation with MOG35-55-expressing APC, it did not affect interferon (IFN)-gamma production by MOG35-55-specific T cells stimulated with anti-CD3 and anti-CD28. These observations suggested that PACAP suppressed induction of EAE primarily via suppression of APC function and inflammatory cytokine production. PACAP may be useful in the future treatment of Th1-mediated autoimmune diseases, such as multiple sclerosis.
Kato
Hideki
H
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Ito
Atsushi
A
Kawanokuchi
Jun
J
Jin
Shijie
S
Mizuno
Tetsuya
T
Ojika
Kosei
K
Ueda
Ryuzou
R
Suzumura
Akio
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000276:immunology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
C495402:Adcyap1 protein, mouse; D018106:CD28 Antigens; D017252:CD3 Complex; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D063308:Myelin-Oligodendrocyte Glycoprotein; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12; D007371:Interferon-gamma