VIP and PACAP differentially regulate the costimulatory activity of resting and activated macrophages through the modulation of B7.1 and B7.2 expression

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activat ing polypeptide (PACAP), two structurally related neuropeptides produced an d/or released within the lymphoid microenvironment. modulate numerous immun e functions. Although primarily antiinflammatory in nature, VIP and PACAP a lso affect resting macrophages. In this study, we report on in vitro and in vivo dual effects of VIP/PACAP on the expression of B7.1 and B7.2 and on t he costimulatory activity for T cells in unstimulated and LPS/IFN-gamma-act ivated macrophages. VIP and PACAP up-regulate B7.2, but not B7.1, expressio n and induce the capacity to stimulate the proliferation of naive T cells i n response to soluble anti-CD3 or allogeneic stimulation. In contrast, both neuropeptides down-regulate B7.1/B7.2 expression on LPS/IFN-gamma-activate d macrophages and inhibit the endotoxin-induced co-stimulatory activity for T cells, Interestingly, both the stimulatory and the inhibitory effects of VIP/PACAP are mediated through the specific receptor VPAC1 and involve the cAMP/protein kinase A transduction pathway, The dual effect on B7.1 and B7 .2 expression occurs at both mRNA and protein level and correlates with the VIP/PACAP regulation of the macrophage costimulatory activity. Through the ir regulatory role for resting and activated macrophages, VIP and PACAP act as endogenous participants in the control of immune homeostasis, Their eff ects depend not only on the timing of their release, but also on the activa tion and differentiation state of the neighboring immune cells.