Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit expression of Fas ligand in activated T lymphocytes by regulating c-Myc, NF-kappa B, NF-AT, and early growth factors 2/3.
J Immunol
; 166(2): 1028-40, 2001 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-11145682
Activation-induced cell death in T cells, a major mechanism for limiting an ongoing immune response, is initiated by Ag reengagement and mediated through Fas/Fas ligand interactions. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), two multifunctional neuropeptides, modulate innate and adaptive immunity. We reported previously that VIP/PACAP protect T cells from activation-induced cell death through down-regulation of Fas ligand (FasL). In this study, we investigate the molecular mechanisms involved in the protective effect of VIP and PACAP. VIP/PACAP reduce in a dose-dependent manner anti-CD3-induced apoptosis in 2B4.11 T cell hybridomas. The protective effect is mediated through the specific type 2 VIP receptor, and the cAMP/protein kinase A pathway. A functional study demonstrates that VIP/PACAP inhibit activation-induced FasL expression. VIP/PACAP inhibit the expression and/or DNA-binding activity of several transcriptional factors involved in FasL expression, i.e., c-myc, NF-kappaB, NF-ATp, and early growth factors (Egr) 2/3. The inhibition of NF-kappaB binding is due to the stabilization of I-kappaB (inhibitory protein that dissociates from NF-kappaB), through the inhibition of I-kappaB kinase alpha activity. Subsequently, p65 nuclear translocation is significantly reduced. The inhibition in NF-ATp binding results from a calcineurin-independent reduction in NF-ATp nuclear translocation. VIP/PACAP inhibit the expression of Egr2 and 3, but not of Egr1. The effects on the transcriptional factors are mediated through type 2 VIP receptor with cAMP as secondary messenger.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonamidas
/
Factores de Transcripción
/
Neuropéptidos
/
Péptido Intestinal Vasoactivo
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Glicoproteínas de Membrana
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Proteínas Nucleares
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Activación de Linfocitos
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Linfocitos T
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FN-kappa B
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Proteínas Proto-Oncogénicas c-myc
Idioma:
En
Revista:
J Immunol
Año:
2001
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos