Vasoactive intestinal peptide inhibits cytokine production in T lymphocytes through cAMP-dependent and cAMP-independent mechanisms

Previous reports indicate that VIP and the structurally related peptide PAC AP inhibit IL-2 and IL-10 production in antigen-stimulated T lymphocytes. I ntracellular cAMP elevation appears to be the primary transduction pathway involved. However, in the lower concentration range, an additional, cAMP-in dependent transduction pathway appears to mediate the VIP inhibition of cyt okine production. Here, we address this question by using VIP agonists and antagonists which act through cAMP-dependent and -independent pathways. The antagonists based on the neurotensin-VIP hybrid molecule did not affect th e inhibitory effect of VIP/PACAP on IL-2 and IL-10 production, confirming t hat astrocytes and T lymphocytes express different receptors, A lipophilic antagonist with increased membrane permeability, partially reversed the inh ibitory effect of VIP/PACAP, forskolin, prostaglandin E2, and 8-bromo-cAMP without significantly affecting cAMP levels, suggesting that it acts downst ream of cAMP. Two VIP agonists inhibit IL-2 and IL-10 production. One of th e agonists increases cAMP, whereas the second one does not induce cAMP/cGMP . Our results indicate that VIP inhibits cytokine production in stimulated CD4+ T cells through two separate mechanisms, which involve both cAMP-depen dent and cAMP-independent transduction pathways. (C) 1999 Elsevier Science B.V. All rights reserved.