Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity.
The structurally related neuropeptides VIP and PACAP are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the production of pro-inflammatory agents (cytokines, chemokines, and nitric oxide), and stimulate the production of the anti-inflammatory cytokine IL-10. These events are mediated through the VIP/PACAP effects on de novo expression or nuclear translocation of several transcription factors, i.e., NFkappaB, CREB, c-Jun, JunB, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine and chemokine modulation, which presumably mediates the protective effect of VIP/PACAP in septic shock. In addition, VIP/PACAP reduce the expression of the co-stimulatory molecules B7.1/B7.2, and the subsequent stimulatory activity of macrophages for T-helper cells. In T-cells expressing specific VIP/PACAP receptors, VIP and PACAP inhibit the expression of FasL through effects on NFkappaB, NFAT, and Egr2/3. The reduction of FasL expression has several biological consequences: inhibition of antigen-induced cell death in CD4 T-cells, inhibition of the FasL-mediated cytotoxicity of CD8 and CD4 effectors against direct and bystander targets, and promotion of long-term memory Th2 cells, through a positive effect on the survival of Th2, but not Th1, effectors. The various biological effects of VIP and PACAP are discussed within the range of a general anti-inflammatory model.
Ganea
Doina
D
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA. dganea@andromeda.rutgers.edu
Delgado
Mario
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000941:Antigens / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D018925:Chemokines / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000276:immunology; D051767:Early Growth Response Protein 2; D053222:Fas Ligand Protein; D006801:Humans; D007110:Immunity, Active / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D060945:Inducible T-Cell Co-Stimulator Ligand; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D050778:NFATC Transcription Factors; D009479:Neuropeptides / Q000276:immunology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000276:immunology* / Q000627:therapeutic use
C495401:ADCYAP1 protein, human; D000276:Adjuvants, Immunologic; D000941:Antigens; D000954:Antigens, Surface; D018122:B7-1 Antigen; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D060945:Inducible T-Cell Co-Stimulator Ligand; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009479:Neuropeptides; D009687:Nuclear Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014157:Transcription Factors; D016753:Interleukin-10; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide