VIP and PACAP induce shift to a Th2 response by upregulating B7.2 expression.
VIP and PACAP, two structurally related neuropeptides produced within the lymphoid microenvironment, modulate several immunological functions. Although primarily anti-inflammatory in nature, VIP and PACAP also affect resting macrophages. In this study, we report on the role of VIP and PACAP on macrophage B7 expression and costimulatory function for antigen-primed CD4+ T cells, and on the macrophage-induced regulation of Th1/Th2 differentiation in vitro and in vivo. VIP and PACAP upregulate B7.2, but not B7.1, MHC class II, or ICAM-1 expression, and activate macrophages to stimulate the proliferation of naïve T cells in response to soluble anti-CD3 or allogeneic stimulation. The stimulatory effect is mediated through the specific receptor VPAC1, and involves the cAMP/PKA pathway as second messengers. The enhancement in B7.2 expression occurs at both mRNA and protein levels, and correlates with the VIP/PACAP induced upregulation of the costimulatory activity of macrophages for antigen-primed CD4+ T cells. VIP/PACAP-treated macrophages gain the ability to induce Th2-type cytokines such as IL-4 and IL-5, and to reduce Th1-type cytokines such as IFN gamma and IL-2. In vivo administration of VIP or PACAP in antigen-immunized mice reduces the numbers of IFN gamma-secreting cells, enhances the numbers of IL-4-secreting cells, and affects the pattern of antigen-specific Ig isotypes. The preferential differentiation into Th2 effector cells induced by VIP/PACAP-treated macrophages is mediated through the upregulation of B7.2 expression. Since Th1-dominated responses are associated with some autoimmune diseases and inflammatory reactions typical of cell-mediated immunity, the VIP/PACAP inhibition of Th1 development may represent an additional mechanism for the general anti-inflammatory activity of the two neuropeptides.
Delgado
M
M
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA. mariodm@eucmos.sim.ucm.es
Leceta
J
J
Sun
W
W
Gomariz
R P
RP
Ganea
D
D
D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen; D066298:In Vitro Techniques; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
C495402:Adcyap1 protein, mouse; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014660:Vasoactive Intestinal Peptide