A triggered release methodology of liposomal contents via the enzyme MMP-9 is described.
Strict regulation of T cell function is imperative to control adaptive immunity, and dysregulation of T cell activation can contribute to infectious and autoimmune diseases. Vasoactive intestinal peptide receptor-1 (VPAC-1), an anti-inflammatory G-protein coupled receptor, has been reported to be downregulated during T cell activation. However, the regulatory mechanisms controlling the expression of VPAC-1 in T cells are not well understood. Therefore, mouse splenic CD4 T cells were treated in complete media+/-anti-CD3 for 24h, total RNA isolated and VPAC-1 levels measured by qPCR. Surprisingly, we discovered that T cells incubated in complete media steadily upregulated VPAC-1 mRNA levels over time (24h). Importantly, CD4 T cells isolated from blood also showed elevated VPAC-1 expression compared to splenic T cells. Collectively, these data support that the vascular environment positively influences VPAC-1 mRNA expression that is negatively regulated by TCR signaling. This research was supported by a national service award (1KO1 DK064828) to G.D., the Center for Protease Research (2P20RR015566), and INBRE (P20 RR016741).
The vasoactive intestinal peptide (VIP) signaling axis constitutes a master "communication coordinator" between cells of the nervous and immune systems. To date, VIP and its two main receptors expressed in T lymphocytes, vasoactive intestinal peptide receptor (VPAC)1 and VPAC2, mediate critical cellular functions regulating adaptive immunity, including arresting CD4 T cells in G1 of the cell cycle, protection from apoptosis and a potent chemotactic recruiter of T cells to the mucosa associated lymphoid compartment of the gastrointestinal tissues. Since the discovery of VIP in 1970, followed by the cloning of VPAC1 and VPAC2 in the early 1990s, this signaling axis has been associated with common human cancers, including leukemia. This review highlights the present day knowledge of the VIP ligand and its receptor expression profile in T cell leukemia and cell lines. Also, there will be a discussion describing how the anti-leukemic DNA binding transcription factor, Ikaros, regulates VIP receptor expression in primary human CD4 T lymphocytes and T cell lymphoblastic cell lines (e.g. Hut-78). Lastly, future goals will be mentioned that are expected to uncover the role of how the VIP signaling axis contributes to human leukemogenesis, and to establish whether the VIP receptor signature expressed by leukemic blasts can provide therapeutic and/or diagnostic information.
SummaryT cells express receptors for neuropeptides that mediate immunological activities. Vasoactive intestinal peptide receptor -1 (VPAC1), the prototypical group II G protein coupled receptor, binds two neuropeptides with high affinity, called vasoactive intestinal peptide and pituitary adenylate cyclase activating peptide. During T cell signaling, VPAC1 mRNA expression levels are significantly downregulated through a Src kinase dependent mechanism, thus altering the sensitivity for these neuropeptides during an immune reaction. Presently, it is unknown whether the mechanism that regulates VPAC1 during T cell signaling involves epigenetic changes. Therefore, we hypothesized that the epigenetic landscape consisting of diacetylation at H3K9/14 and trimethylation at H3K4, two transcriptionally permissive histone modifications, would parallel VPAC1 expression showing high enrichment in untreated T cells, but lower enrichment in α-CD3 treated T cells. To this end, quantitative chromatin immunoprecipitation (ChIP) analysis of H3K9/14ac and H3K4me3 was conducted using purified CD4 + T cells, with CD45R + B cells as a negative control. Our data revealed that these histone modifications at the VPAC1 promoter did indeed parallel its mRNA levels between T and B lymphocytes, but did not decrease during T cell signaling. Collectively, these data strongly imply a euchromatin nuclear position for the VPAC1 locus irrespective of the activation status of T cells.
Proper regulation of the anti‐proliferative G Protein coupled receptor vasoactive intestinal peptide receptor 1 (VPAC1) is important for normal lymphocyte function. VPAC1 mRNA levels are dependent on the activation status of CD4 T cells, as TCR signaling downregulates VPAC1 expression. Ikaros (IK), a transcription factor critical in proper T cell development has been shown to regulate VPAC1 when ectopically overexpressed in NIH‐3T3 cells. Additionally, the VPAC1 locus contains numerous IK binding sites. IK recruits the chromatin remodeling complex NuRD, a HDAC containing multi‐enzyme complex that represses transcription. We hypothesized that IK recruits the NuRD complex upon activation resulting in its downregulation. Binding of IK and HDAC1 to the VPAC1 promoter and gene was queried using chromatin immunoprecipitation. Both were enriched in the VPAC1 locus in an activation dependent manner in the transformed T cell line, HuT 78. This enrichment correlated with the activation induced downregulation of VPAC1. Future studies will overexpress DNA binding, non DNA binding, and alanine/aspartate mutant IK isoforms to determine their effect on IK binding and HDAC1 recruitment. Engagement of the master regulator of lymphopoesis, IK, at the neuropeptide receptor VPAC1 promoter strengthens the neuroimmunomodulation connection at a molecular level. Funding: NIH‐K01 1K01DK064828 and COBRE 2P20RR05566.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.