Selective Gene Expression and Activation-Dependent Regulation of Vasoactive Intestinal Peptide Receptor Type 1 and Type 2 in Human T Cells

Abstract

Vasoactive intestinal peptide (VIP) has potent antiproliferative and anti-inflammatory functions in the immune system. Two structurally distinct G-protein-associated receptors, VIP receptor type 1 (VPAC1) and VIP receptor type 2 (VPAC2), mediate the biological effects of VIP. The regulation of VIP receptor gene expression and the distribution of these receptors in different compartments of the human immune systems are unknown. This study reports, for the first time, a quantitative analysis of VPAC1 and VPAC2 mRNA expression in resting and activated T cells as well as in resting monocytes. Purified human peripheral blood CD4+ T cells and CD8+ T cells were stimulated via the TCR/CD3 receptor complex. Using the novel fluorometric-based kinetic (real-time) RT-PCR, we determined that VPAC1 is constitutively expressed in resting T cells and monocytes; the levels of expression were significantly higher in monocytes and CD4+ T cells than in CD8+ T cells. VPAC1 mRNA expression is significantly higher relative to VPAC2 in resting CD4+ T cells and CD8+ T cells. VPAC2 is expressed at very low levels in resting T cells but is not detectable in resting monocytes. In vitro stimulation of Th cells with soluble anti-CD3 plus PMA induced a T cell activation-dependent down-regulation of VPAC1. VPAC1 is down-regulated under conditions of optimal T cell stimulation. Our results suggest that selective VIP effects on T cell function may be mediated via selective expression of VPAC1 and VPAC2 on T cells and monocytes. Furthermore, down-regulation of VPAC1 in CD4+ T cell subpopulations is highly correlated with T cell activation.

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

“…Previous data reported by Takeba et al (32) had already suggested that VPAC 2 was the only receptor expressed and functional in FLS, based on data limited to RA FLS. Previous data in rodent and human myeloid and lymphoid cells have also shown a different distribution and regulation of VPAC 1 and VPAC 2 (33,34). Monocytes and T cells also constitutively express VPAC 1 , whereas VPAC 2 is inducible by specific cell activation (35)(36)(37).…”

Adaptive Immune Responses During Pregnancy

“…64 Another molecule in the focus of the review by Perez Leiros is vasoactive intestinal peptide (VIP), whose anti-inflammatory and tolerogenic effects were already known. 65 It is now known that VIP levels rise at the fetal-maternal interface at early gestation peaking at placentation begin. 66 Its role in embryogenesis was revealed after observing that its blockade during midgestation ends in induced growth retardation and microcephaly.…”

Vasoactive intestinal peptide signaling axis in human leukemia

“…In naïve, mouse and human CD4 and CD8 T lympho- cytes, the constitutively expressed VPAC1 receptor is 300-500-fold higher than VPAC2 [12,[45][46][47] (unpublished data) at the mRNA and protein levels that appears to be inversely related to the expression level of IL-2. Our laboratory has recently identified the VIP/VPAC1 transcriptome in naïve and activated mouse splenic CD4 T cells.…”

“…In rodent leukemia T cell lines of various etiologies, all cell lines studied exclusively expressed VPAC2, some of which were validated to be functional [57,[82][83][84] . A VPAC2 predominant expression profile in cancer is unusual as VPAC2 expressing tumors are rare [74] , and that the expression profile of healthy peripheral lymphocytes express extremely high VPAC1 at both the mRNA and protein levels [45] . Malignant T cells from ALL patients occur due to a blockade in thymocyte development (thymic in origin), or from a blockade in HSC within the bone marrow (prethymic) [85] .…”