Regulatory effects of vasoactive intestinal peptide on cytokine production in central and peripheral lymphoid organs

Vasoactive intestinal peptide (VIP) belongs to an ever growing family of neuropeptides with immunomodulatory functions. VIP-containing nerve fibers are present in both primary and secondary lymphoid organs, frequently in close proximity to immune cells. In addition, several types of immune cells, including T lymphocytes may function as local VIP sources in the lymphoid microenvironment. VIP released from neuronal and/or non neuronal sources exerts immunomodulatory effects through direct binding to VIP receptors (VIP-Rs), which are expressed on most immune cells. The existence of lymphocytic VIP-Rs has been demonstrated initially through binding studies, and more recently, through molecular biology technology. Both VIP-R1 and VIP-R2, which express high affinity for VIP and related neuropeptides such as the pituitary adenylate cyclase activating peptide (PACAP), are present on lymphocyte subsets, and recent reports suggest that whereas VIP-R1 is expressed constitutively, VIP-R2 expression is induced upon lymphocyte activation. Although VIP affects a variety of immune functions, its primary immunomodulatory function seems to be anti-inflammatory in nature. Whereas a rapid inflammatory response is essential for the ultimate elimination of foreign antigens, its intensity and duration have to be strictly controlled to avoid extensive tissue damage. In this respect, neuropeptides with anti-inflammatory functions such as VIP or the structurally related PACAP, timely released within the lymphoid organs, could play an important physiological role in the down-regulation of the immune response. Cytokines, soluble products of immune cells, play major roles in lymphocyte development, activation, and differentiation. As most cytokines are functionally pleiotropic, redundant, and interdependent, local interactions within the cytokine-neuroendocrine network have significant impact on cytokine production and function. Therefore, the immunomodulatory activities of VIP could be mediated, at least partially, through effects on the production of cytokines. The purpose of this article is to review the existing information regarding the VIP modulation of cytokine expression in immune cells. Both VIP and PACAP downregulate the expression of IL-2 mRNA and protein in T cells activated through the T cell receptor, through reducing both the stability and the de novo transcriptional rate of the IL-2 message. Reduction in the amount of IL-2 generated by the activated CD4+ T cells impacts on both T cell proliferation and on further sequential cytokine production. This is indeed the case with IL-4, which is affected by VIP indirectly, through inhibition of IL-2. In contrast, the inhibitory effect of VIP and PACAP on IL-10 production proceeds through a direct transcriptional event. In contrast to IL-2 which functions solely as a proinflammatory cytokine, IL-4 and IL-10 act as pro- or anti-inflammatory cytokines, depending on their involvement in specific immune responses. Therefore, depending on interactions with the local cytokine network, VIP and related neuropeptides may contribute significantly to controlling the amplitude and timing of the inflammatory response to foreign antigens. Although the role of VIP and related peptides on T cell development has not been investigated yet, the presence of VIP and VIP-Rs in the thymus, and their effect on thymic cytokine production, suggests that VIP and/or PACAP released locally within the thymic environment could also affect T cell development, and therefore participate in the generation and maturation of immune cells.