A functional connection, partially mediated through cytokines and neuropeptides, exists between the neuroendocrine and the immune system. Cytokines released in the CNS regulate the growth and differentiation of neuronal and glial cells, and neuropeptides or neurotransmitters released within the lymphoid organs regulate the development and function of immune cells. The vasoactive intestinal peptide (VIP) and the related neuropeptide the pituitary adenylate cyclase activating polypeptide (PACAP) are present in the lymphoid organs, and act as immunomodulators, exhibiting primarily antiinflammatory activities. The investigators showed previously that VIP and PACAP inhibit T cell- and macrophage-derived cytokine production in vivo and in vitro, that immune cells express VIP/PACAP receptors, and that VIP/PACAP exert protective effects in animal models for septic shock. However, the role of neuropeptides in lymphocyte homeostasis, and particularly in activation-induced T cell apoptosis is not known. The in vitro preliminary studies indicate that VIP/PACAP protect CD4+ T cells against activation-induced cell death (AICD), and suggest the downregulation of Fas ligand (FasL) expression as a possible mechanism. This project proposes to investigate the in vivo and in vitro roles of VIP and PACAP in FasL-induced apoptosis, i.e. in the activation-induced apoptosis of CD4+ T cells, and the cytotoxic activity of T cells against Fas-bearing targets, and to investigate the molecular mechanisms by which VIP and PACAP inhibit FasL expression. Based on their previous studies, and on the preliminary results, they postulate that VIP and PACAP released within the lymphoid organs following antigenic stimulation, regulate the immune response at several stages. First, they act as """"""""macrophage deactivating factors,"""""""" inhibiting the secretion of proinflammatory agents and downregulating the expression of B7. Through their effects on macrophages, VIP and PACAP reduce the further induction of both nonspecific and specific immune responses. In addition, VIP/PACAP inhibit directly IL-2 production by T cells, further reducing T cell proliferation. Also, as proposed here, VIP/PACAP reduce the cytotoxic function of both CD4+ T cells primarily through the downregulation of FasL. Finally, they propose that VIP and PACAP also regulate activation induced T cell apoptosis (AICD), acting as survival factors which might be important for the generation of long-lived memory T cells. Since failure to maintain a balance between cell proliferation and apoptotic cell death leads to the development of either proliferative or degenerative pathological conditions, VIP and PACAP play an important physiological role through the regulation of FasL/Fas-mediated apoptosis. Also, by limiting CD4+ T cell cytoxicity against bystander targets, VIP/PACAP may preserve cell viability in tissues with low MHCII expression such as brain, or of uninfected CD4+ T cells in AIDS.
Showing the most recent 10 out of 33 publications
