Pituitary adenylyl cyclase activating peptide (PACAP) is widely expressed in the embryonic brain at the onset of neurogenesis, and is strongly upregulated in several models of nerve injury. Moreover, high-affinity PACAP receptors are expressed in proliferative zones in the embryonic and postnatal nervous system suggesting that PACAP regulates the development of both neuronal and glial precursors. Tissue culture studies indicate that PACAP exerts a variety of growth factor-like actions that depend on the origin of the cell population and developmental stage. These effects include regulation of proliferation, survival, maturation, neurite outgrowth, and expression of trophic factors, cytokines and trk receptors. The presence of other growth factors can also markedly affect these actions of PACAP, for example, reversing PACAP’s effect from proliferative to antiproliferative. In vivo models now provide additional evidence that PACAP acts in neural development and regeneration.

Neural tube patterning in vertebrates is controlled in part by locally secreted factors that act in a paracrine manner on nearby cells to regulate proliferation and gene expression. We show here by in situ hybridization that genes for the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) and one of its high-affinity receptors (PAC ₁ ) are widely expressed in the mouse neural tube on embryonic day (E) 10.5. Transcripts for the ligand are present in differentiating neurons in much of the neural tube, whereas the receptor gene is expressed in the underlying ventricular zone, most prominently in the alar region and floor plate. PACAP potently increased cAMP levels more than 20-fold in cultured E10.5 hindbrain neuroepithelial cells, suggesting that PACAP activates protein kinase A (PKA) in the neural tube and might act in the process of patterning. Consistent with this possibility, PACAP down-regulated expression of the sonic hedgehog - and PKA-dependent target gene gli -1 in cultured neuroepithelial cells, concomitant with a decrease in DNA synthesis. PACAP is thus an early inducer of cAMP levels in the embryo and may act in the neural tube during patterning to control cell proliferation and gene expression.

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a widely expressed neuropeptide originally discovered in the hypothalamus. It closely resembles vasoactive intestinal peptide (VIP), a neuropeptide well known to inhibit macrophage activity, promote Th2-type responses, and enhance regulatory T cell (Treg) production. Recent studies have shown that administration of PACAP, like VIP, can attenuate dramatically the clinical and pathological features of murine models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. However, specific roles (if any) of endogenous VIP and PACAP in the protection against autoimmune diseases have not been explored. Here, we subjected PACAP-deficient mice to myelin oligodendrocyte glycoprotein (MOG_35–55)-induced EAE. MOG immunization of PACAP-deficient mice triggered heightened clinical and pathological manifestations of EAE compared to wild-type mice. The increased sensitivity was accompanied by enhanced mRNA expression of proinflammatory cytokines (TNFα, IL-6, IFN-γ, IL-12p35, IL-23p19, and IL-17), chemokines (MCP-1/CCL2, MIP-1α/CCL3, and RANTES/CCL5), and chemotactic factor receptors (CCR1, CCR2, and CCR5), but downregulation of the anti-inflammatory cytokines (IL-4, IL-10, and TGF-β) in the spinal cord. Moreover, the abundance of CD4⁺CD25⁺FoxP3⁺Tregs in lymph nodes and levels of FoxP3 mRNA in the spinal cord were also diminished. The reduction in Tregs was associated with increased proliferation and decreased TGF-β secretion in lymph node cultures stimulated with MOG. These results demonstrate that endogenous PACAP provides protection in EAE and identify PACAP as an intrinsic regulator of Treg abundance after inflammation.