Vasoactive intestinal peptide inhibits interleukin (IL)-2 and IL-4 production through different molecular mechanisms in T cells activated via the T cell receptor/CD3 complex

https://doi.org/10.1016/0165-5728(93)90059-8Get rights and content

Abstract

The neuropeptide vasoactive intestinal peptide (VIP) has been reported previously to inhibit cell proliferation and interleukin (IL)-2 production in mitogen-stimulated T lymphocytes. In physiological conditions, T lymphocytes are specifically activated by antigen-binding through the T cell receptor (TCR). Here we report on the effect of VIP and related peptides on IL-2 and IL-4 production of murine T lymphocytes stimulated through the TCR. VIP inhibited IL-2 and IL-4 production (both at the level of protein concentration and biological activity) by unfractionated spleen cells or purified CD4+ T cells stimulated with either anti-CD3 monoclonal antibodies (mAbs) or with anti-CD3 mAbs plus phorbol esters. The inhibition was dose-dependent, and specific, since structurally related peptides such as secretin and glucagon had little or no inhibitory activity. VIP inhibited IL-2 and IL-4 production through different molecular mechanisms. IL-2 production was regulated at a transcriptional level through the downregulation of IL-2 mRNA, whereas the production of IL-4 was modulated at a posttranscriptional level.

References (52)

  • C.A. Ottaway et al.

    Vasoactive intestinal peptide-containing nerves in Peyer's patches

    Brain Behav. Immun.

    (1987)
  • P.W.H.I. Parren et al.

    Induction of T-cell proliferation by recombinant mouse and chimeric mouse/human anti-CD3 monoclonal antibodies

    Res. Immunol.

    (1991)
  • P. Robberecht et al.

    Variable stimulation of adenylate cyclase activity by vasoactive intestinal-like peptide and β-adrenergic agonist in murine T-cell lymphomas of immature, helper, and cytotoxic types

    Immunobiology

    (1989)
  • M.R. Ruff et al.

    CD4 receptor binding peptides that block HIV infectivity cause human monocyte chemotaxis. Relationship to vasoactive intestinal peptide

    FEBS Lett.

    (1987)
  • J.J. Segura et al.

    Stimulatory effect of vasoactive intestinal peptide (VIP) on cyclic AMP production in rat peritoneal macrophages

    Regul. Prpt.

    (1992)
  • H. Tada et al.

    An improved colorimetric assay for interleukin 2

    J. Immunol. Methods

    (1986)
  • A.Y. Tsygankov et al.

    Inhibition of anti-CD3-induced T cell proliferation by crosslinking of stimulatory antibodies in the presence of PMA and interleukin 2

    Cell. Immunol.

    (1992)
  • P. Wiik et al.

    Binding of vasoactive intestinal peptide (VIP) by human blood monocytes: demonstration of specific binding sites

    Regul. Pept.

    (1985)
  • C.L. Wood et al.

    Covalent cross-linking of vasoactive intestinal polypeptide to its receptors on intact human lymphoblasts

    J. Biol. Chem.

    (1985)
  • E.D. Anastassiou et al.

    Prostaglandin E2 and other cyclic AMP-elevating agents modulate IL-2 and IL-2Rα gene expression at multiple levels

    J. Immunol.

    (1992)
  • L. Bondesson et al.

    Dual effects of vasoactive intestinal peptide (VIP) on leucocyte migration

    Acta Physiol. Scand.

    (1991)
  • F. Boudard et al.

    Inhibition of mouse T cell proliferation by CGRP and VIP: effects of these neuropeptides on IL-2 production and cAMP synthesis

    J. Neurosci. Res.

    (1991)
  • S. Cardell et al.

    IL 2, 4 and 5 are sequentially produced in mitogen-stimulated murine spleen cell cultures

    Eur. J. Immunol.

    (1990)
  • A.M. Danek et al.

    Specific binding sites for vasoactive intestinal peptide on nonadherent peripheral blood lymphocytes

    J. Immunol.

    (1983)
  • T. Epsevic et al.

    Inhibition of cytokine production by cyclosporin A and transforming growth factor β

    J. Exp. Med.

    (1987)
  • D.L. Felten et al.

    Noradrenergic and peptidergic innervation of lymphoid tissue

    J. Immunol.

    (1985)
  • Cited by (82)

    • Characterization and use of a rabbit-anti-mouse VPAC1 antibody by flow cytometry

      2012, Journal of Immunological Methods
      Citation Excerpt :

      A functional example would be T cell homing to Peyer's Patches, as a lowering of VIP binding sites after mouse CD4 T cell activation is associated with reduced T cell homing (Ottaway, 1984). In addition, it has been shown that VPAC1 signaling can suppress the activation of CD4 T cells by inhibiting IL-2 and IL-4 expression thereby bolstering the T cell activation threshold and inhibiting bystander T cell activation (Sun and Ganea, 1993). Also, regulatory T cells (CD4+/CD25+/FOXP3+) have been shown to be enhanced by VIP/VPAC1 signal transduction.

    • TCR signaling and environment affect vasoactive intestinal peptide receptor-1 (VPAC-1) expression in primary mouse CD4 T cells

      2008, Brain, Behavior, and Immunity
      Citation Excerpt :

      In contrast, 5 ng/ml PMA and 1 μg/ml ionomycin showed a robust increase in IL-2 secretion (1476 pg/ml, n = 2) confirming that these naïve CD4 T cells can be appropriately activated (Fig. 1b). Anti-CD3 ± anti-CD28 treatment resulted in significantly elevated IL-2 levels (120 and 250 pg/ml, respectively; n = 5) and indicates that this ex vivo treatment successfully triggers TCR signaling and IL-2 secretion (Sun and Ganea, 1993; Schillace et al., 2005). To confirm the accuracy and precision of our qPCR procedure, we quantitated VPAC-1 mRNA levels from eleven different mouse tissues.

    • Morphological relationships between peptidergic nerve fibers and immunoglobulin A-producing lymphocytes in the mouse intestine

      2008, Brain, Behavior, and Immunity
      Citation Excerpt :

      VIP receptors are expressed not only on the IgA lymphocytes, but also on the T cells in the epithelium and the LP of the intestine (Qian et al., 2001). On the other hand, VIP inhibits IL-2 and IL-10 production in T cells (Sun and Ganea, 1993; Martinez et al., 1996; Wang et al., 1996), whereas it promotes the production of IL-5 and IFN-γ (Mathew et al., 1992; Jabrane-Ferrat et al., 1999), and increases mRNA levels of IL-8 to increase secretion (Toumi et al., 2004). Therefore, it is possible that neuropeptides liberated from varicosities regulate IgA synthesis in lymphocytes via T cell activity.

    View all citing articles on Scopus
    #

    In partial fulfilment of the requirements for the degree of Doctor in Philosophy in the Graduate College, Rutgers University, Newark, NJ 07102, USA.

    View full text