Vasoactive intestinal peptide signaling axis in human leukemia

Abstract

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.

Th17 polarization of memory Th cells in early arthritis: the vasoactive intestinal peptide effect

“…It functions through binding to its specific receptors VPAC 1 and VPAC 2 . Both receptors are expressed in lymphoid cells, specifically in CD4 T cells [19][20][21]. However, whereas VPAC 1 is constitutively expressed, VPAC 2 is induced after cell activation [22].…”

RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal peptide (VIP) shows a shift in metabolic state and innate immune functions that coincide with healing

“…The up-regulation of Ikaros here may indicate a decline in lymphocyte proliferation after treatment with VIP. Interestingly, Ikaros has been shown to up-regulate VIP receptor expression through the 12 putative binding sites in the promotor regions in each of the two VIP receptor genes (Dorsam, Benton, Failing, & Batra, 2011). Patients in the study showed an up-regulation in all 5 Ikaros isoforms (Ikz1; +1.24 fold, Ikz2; +1.41, Ikz3; +1.41, Ikz4; +1.38, and Ikz5; +1.18).…”

Epigenetic control of cancer by neuropeptides

“…In a previous study, VIP receptor antagonists facilitated chemotherapeutic agents to cause apoptosis in certain cancer cell lines (33); VIP is cell context-dependent and is known to contribute to leukemogenesis (34). There is reported similarity of VIP with pituitary adenylate cyclase, which belongs to the secretin family.…”

“…VIP is produced by various cells, however, its primary location is within neurons; this peptide is expressed in the peripheral and central nervous systems, as well as in certain tumors (3,(33)(34)(35)(36). In a previous study, VIP receptor antagonists facilitated chemotherapeutic agents to cause apoptosis in certain cancer cell lines (33); VIP is cell context-dependent and is known to contribute to leukemogenesis (34).…”