Inhibitory effect of pasireotide and octreotide on lymphocyte activation
Introduction
Somatostatin (SS) acts as a neurotransmitter and paracrine/autocrine regulator or, more specifically, as a hormone which regulates several physiological processes, such as secretion, neuromodulation, smooth muscle contractility, nutrient absorption and cell growth (Guillemin, 1978, Lamberts et al., 1996, Patel, 1999). The physiological effects of SS are predominantly inhibitory and all the actions are mediated by interaction with five different types of high-affinity plasma membrane receptors (SSTRs), which are widely expressed through human tissues (Patel, 1999). SSTR1 to 5 are encoded by five non-allelic genes and are intronless, apart from SSTR2, which displays two different splice variants (Patel, 1999, Meyerhof, 1998). SSTRs have seven α-helical transmembrane domains and are coupled to guanine–nucleotide-binding proteins (G-proteins) (Patel, 1999, Meyerhof, 1998) which may trigger several pathways on activation. Down-stream signalling includes modulation of adenylyl cyclase (AC) (SSTR1-5), phosphotyrosine phosphatases (PTPs) (SSTR1, 2 and 3) and mytogen activated protein kinase (MAPK) (SSTR4), as well as calcium and potassium channels and the sodium-proton antiporter (Bruns et al., 1994). All SSTRs inhibit AC, resulting in decreased intracellular cyclic AMP levels (Patel, 1999) which, in turn, influence the activity of protein kinase A (PKA) and, subsequently, of the cAMP response-element binding protein, CREB (Florio et al., 1996). Accordingly, all human SSTR subtypes can be coupled to different phospholipase C (PLC) isoforms (Akbar et al., 1994). In most cells, calcium signalling is down-regulated by SSTR activation, resulting in membrane hyperpolarization (Patel, 1999). However, the signalling events prevailing in specific tissues depend on the distribution of SSTRs and on the correlated signalling elements. The somatostatin receptors (SSTR1-5) exert their antiproliferative action by inducing G0–G1 cell cycle arrest (Cheung and Boyages, 1995) or G2-M apoptosis (Srikant, 1995). Somatostatin modulates cell proliferation, differentiation and apoptosis and stops cell cycle progression by inducing the cyclin-dependent kinase inhibitor p27/Kip1 (Pages et al., 1999, Medina et al., 1999). The mechanisms of somatostatin-induced apoptosis are still mostly unexplained. SRIF has a very short plasma half-life of < 3 min (Patel, 1983), but metabolically stable compounds with SRIF-like properties have been synthesised and are currently used in clinical practice. In 1990, octreotide (SMS 201-995) was one of the first SRIF analogues to be synthesised and used in clinical practice. Octreotide triggers cytostatic and cytotoxic effects and has a general inhibitory effect on the secretion mediated through interaction with somatostatin receptors. The long-acting SST analogues, such pasireotide and SMS 201-995, have been reported to inhibit human lymphocyte proliferation (Perego et al., 1998). These analogues have different affinities for SSTR subtypes: pasireotide has a high affinity for SSTRs 1, 2, 3, and 5 (Bruns et al., 2002) while octreotide (SMS 201-995) binds SSTRs 2 and 5 and, to a lesser extent, SSTR3 (Patel, 1999). Compared with octreotide, pasireotide has an affinity which is 30 times greater with SSTR1, 5 times greater with SSTR3 and 40-times greater with SST5 receptors while its affinity to SSTR2 is 2.5 times lower (Hipkin et al., 1997). Moreover, SSTR internalization, desensitization and/or receptor crosstalk play an important role in determining the tissue specific response to SRIF and its analogues (Liu et al., 2005).
The aims of the present study are two-fold and are to compare the ability of these long-acting somatostatin analogues to inhibit lymphocyte proliferation and to shed some light on the mechanism involved.
Section snippets
Isolation of peripheral blood lymphocytes and proliferation assay
Human peripheral blood lymphocytes (PBL) from young healthy donors (20–45 years), were obtained from the Blood Bank of the “Istituto Nazionale per lo Studio e la Cura dei Tumori”, Milan Italy. Mononuclear cells were isolated by Lympholite (Hyclone, Logan, UT, USA) density gradient centrifugation. Cells recovered from the interface were washed with HBSS (Sigma Aldrich, Saint-Louis, Mo, USA) and suspended in RPMI 1640 medium (Sigma Aldrich, Saint-Louis, Mo, USA) supplemented with 5%
Results
The antiproliferative effect of pasireotide and octreotide on human lymphocyte proliferation was studied on human PBL activated by alloantigen (MLR). Both analogues inhibited human lymphocytes but, while the optimal dose for pasireotide is 10− 12 M, SMS significantly inhibits lymphocyte proliferation from 10− 11 to 10− 9 M (Fig. 1), this discrepancy is maybe due to the different receptor affinities of these analogues. MLR supernatants were analysed for cytokine production and in order to do so,
Discussion
Somatostatin regulates the function of the central and peripheral nervous system, the endocrine and exocrine organs, as well as the vascular and immune systems. These actions are mediated by specific membrane SST receptors coupled to multiple signal transduction pathways, which elicit antisecretory as well as antiproliferative responses (Patel et al., 1995, Reisine and Bell, 1995). There is also evidence for different, although not mutually exclusive, pathways of intracellular signalling of
References (30)
- et al.
Phopholipase C activation and Ca 2+ mobilization by cloned human somatostatin receptor subtype 1–5 in transfected COS-7 cells
FEBS Lett.
(1994) - et al.
Regulation of human peripheral blood lymphocytes IL-10 BY SMS 201-995
J. Neuroimmunol.
(2004) - et al.
Somatostatin inhibits PC C13 thyroid cell proliferation through the modulation of phosphotyrosine phophatase activity-impairment of the somatostatinergirc effects by stable expression of EIA viral oncogene
J. Biol. Chem.
(1996) - et al.
Agonist-induced desensitization, internalization, and phosphorylation of the sst2A somatostatin receptor
J. Biol. Chem.
(1997) Peptides as regulators of the immune system: emphasis on somatostatin
Peptides
(2000)- et al.
The apoptotic effect of somatostatin analogue SMS 201-995 on human lymphocytes
J. Neuroimmunol.
(2002) - et al.
Sst2 somatostatin receptor mediates cell cycle arrest and induction of p27 (Kip 1). Evidence for the role of SHP-1
J. Biol. Chem.
(1999) Somatostatin and its receptor family
Front. Neuroendocrinol.
(1999)- et al.
Mini review: the somatostatin receptor family
Life Sci.
(1995) - et al.
Evidence that SMS 201-995 enhances the immunosuppressive effect of FK506 Intern
J. Immunopharmacol.
(1998)
Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A)
J. Biol. Chem.
Cell cycle dependent induction of apoptosis by somatostatin analog SMS 201-995 in AtT-20 mouse pituitary cells
Biochem. Biophys. Res. Commun.
Molecular pharmacology of somatostatin receptor subtype
Ann. N.Y. Acad. Sci.
SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile
Eur. J. Endocrinol.
Somatostatin 14 and its analog octreotide exert a cytostatic effect on GH3 rat pituitary tumor cell proliferation via a transient G0/G1 cell cycle block
Endocrinology
Cited by (29)
The association between treatment and systemic inflammation in acromegaly
2021, Growth Hormone and IGF ResearchCitation Excerpt :The decline in concentrations of circulating inflammatory markers and pro-inflammatory cytokine production, and the increase of IL10 production at T1, might be caused by the combined effects of (partial) disease control and SSA treatment. At T2 we observed slightly higher levels of pro-inflammatory markers compared to T1, which was not explained by residual disease activity as those patients had controlled disease, but might be explained by the cessation of SSAs and therefore absence of their suggested anti-inflammatory effects [36–38]. Endothelial dysfunction is considered the earliest stage of atherosclerotic disease [39], and has been reported in acromegaly patients [6,7,9,40].
Clinical applications of Gallium-68
2013, Applied Radiation and IsotopesCitation Excerpt :Whereas the thyrotropin receptor (TSHR) activates AC with a subsequent increase of cyclic adenosine monophosphate (cAMP), SSTR activation inhibits the AC/cAMP pathway (de Jong et al., 1997). It has been shown that there is a close association between SSTR and TSHR expression (Lattuada et al., 2007; Medina et al., 1999). All patients with thyroid autonomy and most patients with active Hashimoto's disease demonstrate increased 68Ga-DOTATOC uptake in the thyroid gland (Lincke et al., 2009, 2011).
Management of Enterocutaneous Fistulas
2011, Surgical Clinics of North AmericaCitation Excerpt :If a patient has a condition precluding spontaneous fistula closure, octreotide will only increase cost without affecting outcome, (see Box 2). In addition, octreotide inhibits growth hormone, thereby potentially inhibiting immune function.32–34 However, there are no clinical studies confirming or excluding this possibility.
Enteric Fistulas: Principles of Management
2009, Journal of the American College of SurgeonsCitation Excerpt :No evidence exists that pharmacological manipulation improves fistula closure rates.33 Octreotide has the potential to adversely affect immune function as a result of growth hormone inhibition.34-36 There are no clinical data to confirm or exclude this possibility.
Somatostatin-SSTR3-GSK3 modulates human T-cell responses by inhibiting OXPHOS
2024, Frontiers in Immunology