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

摘要

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 YIP and PACAP. YIP/PACAP reduce in a dose-dependent manner anti-CD3-induced apoptosis in 284.11 T cell hybridomas. The protective effect is mediated through the specific type 2 YIP receptor, and the cAMP/protein kinase A pathway. A functional study demonstrates that YIP/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-KB, NF-ATp, and early growth factors (Egr) 2/3. The inhibition of NF-KB binding is due to the stabilization of I-K8 (inhibitory protein that dissociates from NF-KB), through the inhibition of I-KB kinase a activity. Subsequently, p65 nuclear translo- cation is significantly reduced. The inhibition in NF-ATp binding results from a calcineurin-independent reduction in NF-ATp nuclear translocation. YIP/PACAP inhibit the expression ofEgr2 and 3, but not of Egr1. The effects on the transcriptional factors are mediated through type 2 VIP receptor with cAMP as secondary messenger.