Down-regulation of cytokine expression in murine lymphocytes by PACAP and VIP.

Neuropeptides, such as VIP and PACAP, released or produced in the microenvironment of the primary and secondary lymphoid organs, could affect a variety of immune responses through the regulation of cytokine expression. VIP has been previously shown to inhibit IL-2, IL-4, and IL-10 production in murine lymphocytes stimulated through the TCR-associated CD3 complex. This study shows that, similar to VIP, PACAP-38 inhibits IL-2 production in T lymphocytes. Comparisons with forskolin, a known cAMP inducer, suggest that the increase in intracellular cAMP represents at least one of the transduction pathways involved in IL-2 inhibition, especially in the higher range of neuropeptide concentration. Studies of the detailed molecular mechanisms involved in the regulation of IL-2 expression indicate that reduction of de novo transcription and destabilization of the message contribute to the reduction of steady-state IL-2 mRNA levels following VIP treatment. Examination of several IL-2 transcriptional factors indicates that only NFAT is down-regulated by VIP. Neuropeptides, such as VIP and PACAP, which specifically modulate the expression of various cytokines, could play an important role in the intricate cytokine network controlling local immune responses.