Wang H Y, Jiang X, Gozes I, Fridkin M, Brenneman D E, Ganea D
Department of Biological Sciences, Rutgers University, NJ 07102, USA.
Regul Pept. 1999 Oct 22;84(1-3):55-67. doi: 10.1016/s0167-0115(99)00068-3.
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.
先前的报告表明，血管活性肠肽（VIP）和结构相关肽垂体腺苷酸环化酶激活肽（PACAP）可抑制抗原刺激的T淋巴细胞中白细胞介素-2（IL-2）和白细胞介素-10（IL-10）的产生。细胞内cAMP升高似乎是主要的转导途径。然而，在较低浓度范围内，另一条不依赖cAMP的转导途径似乎介导了VIP对细胞因子产生的抑制作用。在此，我们通过使用通过依赖cAMP和不依赖cAMP途径起作用的VIP激动剂和拮抗剂来解决这个问题。基于神经降压素-VIP杂合分子的拮抗剂不影响VIP/PACAP对IL-2和IL-10产生的抑制作用，证实星形胶质细胞和T淋巴细胞表达不同的受体。一种具有增加膜通透性的亲脂性拮抗剂部分逆转了VIP/PACAP、福斯可林、前列腺素E2和8-溴-cAMP的抑制作用，而对cAMP水平无明显影响，表明它在cAMP下游起作用。两种VIP激动剂抑制IL-2和IL-10的产生。其中一种激动剂增加cAMP，而另一种不诱导cAMP/cGMP。我们的结果表明，VIP通过两种独立机制抑制刺激的CD4+T细胞中细胞因子的产生，这两种机制涉及依赖cAMP和不依赖cAMP的转导途径。
