VIP/PACAP preferentially attract Th2 effectors through differential regulation of chemokine production by dendritic cells

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Abstract
The neuropeptides vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) are potent immunomodulatory agents, acting as general anti-inflammatory factors. VIP, produced and secreted by Th2 cells following antigen stimulation, participates in a Th2 autoregulatory loop, promoting Th2-type responses through several nonexcluding mechanisms. VIP and PACAP affect the differentiation of CD4+ T cells directly and indirectly through antigen-presenting cells and promote the proliferation and/or survival of the Th2 effectors. Th1 and Th2 effectors express different chemokine receptors that control migration in response to various chemokines. In this study, we investigated the effects of VIP/PACAP on the production of CXCL10 (a Th1 chemokine) and of CCL22 (a Th2 chemokine) by bone marrow-derived dendritic cells. We found that VIP and PACAP inhibit CXCL10, while promoting CCL22 production, and that the effects are mediated through the VPAC1 receptor and involve cAMP/PKA as intracellular messengers. The induction of CCL22 and the suppression of CXCL10 in VIP/PACAP-treated dendritic cells results in the preferential chemoattraction of Th2 effectors both in vivo and in vitro. This is in agreement with the general Th2 bias induced by the two neuropeptides and adds an important parameter to their immunomodulatory function. By promoting Th2 migration, and preventing or reducing Th1 infiltration in inflammatory foci and sites of antigen presentation, VIP and PACAP help in resolving acute inflammatory processes and contribute to the prevention of chronic inflammation.