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.
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.
Delgado
M
M
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Ganea
D
D
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D000242:Cyclic AMP / Q000502:physiology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D051767:Early Growth Response Protein 2; D051776:Early Growth Response Protein 3; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006825:Hybridomas; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D007939:Leukemia L1210; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050778:NFATC Transcription Factors; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011401:Promoter Regions, Genetic / Q000276:immunology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018005:Receptors, Vasoactive Intestinal Peptide / Q000502:physiology; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D020218:Response Elements / Q000276:immunology; D015290:Second Messenger Systems / Q000276:immunology; D013449:Sulfonamides; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
C495402:Adcyap1 protein, mouse; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C497369:Egr3 protein, mouse; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D007546:Isoquinolines; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009479:Neuropeptides; C000606205:Nfkbia protein, mouse; D009687:Nuclear Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016271:Proto-Oncogene Proteins c-myc; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D013449:Sulfonamides; D051996:Transcription Factor RelA; D014157:Transcription Factors; D019014:fas Receptor; D000072000:NF-KappaB Inhibitor alpha; D051776:Early Growth Response Protein 3; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide