Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: Players in innate and adaptive immunity

Recent reports identified and described neural pathways, both hard-wiring and soluble mediators, that control and adjust the peripheral immune response. Immune organs are innervated by fibers rich in neurotranstiritters and neuropeptides released in inflammatory conditions. Here we focus on the immunomodulatory role of two neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating potypeptide (PACAP). VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and immune cells express receptors for VIP/PACAP. VlP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4+ T cells. In terms of adaptive immunity, VlP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors, are discussed.