Somatostatin receptor distribution and function in immune system
Introduction
Immune cells and immune response are significantly influenced by the neuroendocrine system. The nervous system displays a specialised, local immunoreactivity, and central (thymus and bone marrow) and peripheral (lymph nodes, spleen, tonsils) lymphoid organs are innervated by both sympathethic and parasympathethic components. In addition, lymphoid organs contain neuroendocrine cells producing the major chemical categories of messengers, hormones or neuropeptides, which exert locally their paracrine activities through their receptors on immune cells. Therefore, primary and secondary lymphoid organs can be considered preferential sites of immune-neuroendocrine interactions. However, these systems may also regulate each other and communicate via direct cell-to-cell contact and by the production of cytochines and chemokines from both immune and neuroendocrine cells [1]. Among the hormone and neuropeptides involved in regulating immune cell activities, particular emphasis goes on somatostatin (SS) which seems to predominantly exert an inhibitory action on immune functions (Table 1) [1], [2], [3].
SS is secreted in two biologically active forms, SS-14 and the amino-terminally extended 28 amino acid SS-28. The neuropeptide acts on its target cells through five specific G-protein coupled transmembrane receptors (SSRs), initially identified by ligand-binding studies using iodinated SS and/or the more stable synthetic analogues (octreotide, lanreotide and vapreotide). The genes of the five different SSR subtypes code-named sst1–5 have been cloned and characterized [4], [5], [6]. SSR display a tissue specific distribution [4], [5], but the majority of SS-target tissues express multiple SSR subtypes simultaneously [7]. Recently, the availability of antibodies specific for individual SSR, allowed to investigate by immunohistochemistry and immunofluorescence the cellular localisation of the different subtype [8], [9], [10]. SS inhibits hormone secretion and cell proliferation in a variety of neuroendocrine and non-neuroendocrine tissues and has a modulatory actions on the response of various cells to endocrine stimulation [11], [12], [13]. The recent advances in the identification of novel SSR-specific analogs and antagonists permit the study of the role of individual receptor subtypes in regulating cell production as well as cell proliferation [14], [15], [16], [17]. Although the different SSR subtypes are 40–60% structurally homologous, each subtype mediates different biological actions of SS. Depending on the cell type, the five SSR subtypes are coupled to a variety of signal transduction pathways, including adenylate and guanylate cyclase, phospholipase A2 and C, K+ and Ca2+ channels, Na+–H+ exchanger, Src, Erk1/2, p38 mitogen-activated protein kinases, and tyrosine phosphatases [13]. Although the evidence is preliminary, some specific physiological roles can be attributed to SSR subtypes. For example, in humans, sst2 and sst5 are involved in controlling growth hormone release, and sst5 appears to be important in modulating insulin and glucagon release. As far as cell proliferation is concerned, sst3, and to a lesser extent sst2, can induce apoptosis, whereas sst1, sst4 and sst5 have an inhibitory effect on the cell cycle [13]. SS has a plasma half-life less than 3 min, therefore synthetic analogs with a longer half-life and resistant to proteolytic degradation have been synthesised for clinical application. Octreotide, lanreotide and vapreotide have been already introduced in the clinical practice and all bind sst2, sst3 and sst5, but not sst1 and sst4.
Section snippets
Somatostatin and cortistatin in immune cells
SS-14 and SS-28 have been identified in rat lymphoid organs using anti-SS antibodies and is secreted in vitro by splenic rat lymphocytes [18], [19]. Rat leukaemia cells also exhibit SS immunoreactivity [20]. Activated macrophages isolated from granulomas of Schistosoma mansoni-infected mice seem also to locally produce SS [21]. In a recent study, SS has been found highly expressed in both cortical and medullary epithelial cells in murine thymus [22]. In humans, SS has been localised in the
Somatostatin receptor subtype expression in immune cells
Starting since the early eighties, binding studies using both fluorescent and radiolabelled SS demonstrated the presence of SS-binding sites on immune cells. In enriched preparations of human monocytes and lymphocytes, the number of SSR seemed higher in the monocyte fraction compared the lymphocytes [27]. Whereas, a single class of low affinity SSR was found on human mitogen-activated peripheral blood lymphocytes and two classes, low and high affinity, on lymphoblastic leukaemia cells [28].
Neoplasms
SSR scintigraphy using radiolabelled SS analogs allow the visualisation of SS-binding sites in several immune disorders [50], [51], [52]. Moreover, SSR have been detected in vivo and in vitro in both T and B cells from non-Hodgkin’s lymphoma and Hodgkin’s disease and their metastasis [53], [54], [55], [56]. Definitively, in vivo imaging using [-DTPA0]octreotide may improve the accuracy of staging procedures in patients with malignant lymphomas. Using in vitro autoradiography, SSR were
Conclusions
SSR subtypes appear to be differentially expressed on specific cell subsets within the organs of the immune system. The expression of neuropeptide receptors on immune cells is dynamically regulated and may depend on the traffic of these cells through and within lymphoid structure and homing in tissues. SS may be involved in the regulation of a number of different immune cells but it may also regulate diverse functional aspects in the same type of immune cells (e.g. proliferation, secretion,
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