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 PACAP, inhibit IL-2 and IL-10 production in antigen-stimulated T lymphocytes. Intracellular cAMP elevation appears to be the primary transduction pathway involved. However, in the lower concentration range, an additional, cAMP-independent transduction pathway appears to mediate the VIP inhibition of cytokine 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 the inhibitory effect of VIP/PACAP on IL-2 and IL-10 production, confirming that astrocytes and T lymphocytes express different receptors. A lipophilic antagonist with increased membrane permeability, partially reversed the inhibitory effect of VIP/PACAP, forskolin, prostaglandin E2, and 8-bromo-cAMP without significantly affecting cAMP levels, suggesting that it acts downstream of cAMP. Two VIP agonists inhibit IL-2 and IL-10 production. One of the 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-dependent and cAMP-independent transduction pathways.
Wang
H Y
HY
Department of Biological Sciences, Rutgers University, NJ 07102, USA.
Jiang
X
X
Gozes
I
I
Fridkin
M
M
Brenneman
D E
DE
Ganea
D
D
D000818:Animals; D002478:Cells, Cultured; D003208:Concanavalin A; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000819:agonists / Q000494:pharmacology*
D007376:Interleukin-2; D003208:Concanavalin A; D016753:Interleukin-10; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP