1: J Immunol. 2001 Jan 15;166(2):1028-40. 

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.

Delgado M, Ganea D.

Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.

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.

PMID: 11145682 [PubMed - indexed for MEDLINE]


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