Vasopressin (VP) has emerged in recent years as a very important immunoregulatory peptide of the hypothalamus. VP is capable of maintaining immune function, both innate and adaptive immunity. This is due to the ability of VP to stimulate both the hypothalamic-pituitary-adrenal (HPA) axis and prolactin (PRL) secretion. The HPA axis is important for innate immune function, whereas PRL maintains adaptive immunocompetence. VP also has a direct regulatory effect on lymphocytes, which remains to be elucidated. During acute illness or acute phase responses (APR), VP will rise along with corticotropin-releasing hormone (CRH). In this case CRH is in control of the systemic inflammatory process, and VP has a supportive role. Innate immunity is amplified by glucocorticoids and catecholamines, whereas adaptive immune function is suppressed. During chronic inflammation CRH is repressed and VP takes over as a primary hypothalamic immunoregulator. At this stage VP gradually restores homeostasis by maintaining both the HPA axis and PRL in balance, and hence restores normal immune function and leads to healing of the organism. Therefore, the two hypothalamic immunoregulatory peptides, CRH and VP have different functions. CRH plays an important function in acute phase responses, whereas VP supports APR, but it is really the hypothalamic regulator of healing and of normal immune function.
The activation of the renin-angiotensin system and the hypothalamic-pituitary-adrenocortical axis has a fundamental role in the stress response. Stressors increase the secretion of norepinephrine and epinephrine from the sympathetic nervous system and adrenal medulla, the release of CRH and VP from parvicellular neurons into the portal circulation, and seconds later, the secretion of pituitary ACTH, leading to secretion of glucocorticoids by the adrenal gland. CRH coordinates the endocrine, autonomic, behavioral and immune responses to stress and also acts as a neurotransmitter or neuromodulator in the amygdala, dorsal raphe nucleus, hippocampus and locus coeruleus. VP, serotonin (5-hydroxytryptamine or 5-HT) and catecholamines (CAT) are additional classical mediators. Other neuropeptides/neuromodulators involved are substance P, vasoactive intestinal polypeptide, neuropeptide Y and cholecystokinin . Cytokines, such as interleukin (IL)-1 stimulate CRH and VP gene expression, and are implicated in immune-neuroendocrine regulation. Expression profiles of the CRH and VP genes are not uniform after stress exposure, and the VP gene appears to be more sensitive to glucocorticoid suppression .
Gene expression and regulation
Immunoreactive CRH was detectable in all extracts of spleen and thymus of rats  and cytoplasmic or nuclear extracts of human peripheral blood lymphocytes contained VP . IL-1beta (100 U/ml) significantly potentiated the acetylcholine-induced VP release. This effect was completely blocked in the presence of neutralizing antibodies to IL-1beta, atropine or mecamylamine. IL-6 potentiated acetylcholine-induced VP release in rats . In IL-1beta-treated rats the change in body temperature, and ventral septal area VP release were negatively correlated . In male rats the ACTH response to IL-1beta was significantly reduced by both anti-CRH and anti-VP antisera, compared to the levels after normal rabbit serum . Similarly in rats the IL-6-induced ACTH response was significantly suppressed by both anti-CRH and anti-VP antibodies. The tumor necrosis factor (TNF) – alpha-induced ACTH response was not significantly affected by anti-VP antibody, although anti-CRH antibody could suppress the response .
The IL-1beta-induced intracellular events in oxytocin (OT) and VP neurons in PVN are quite different. The OT neurons are mainly activated via Fos without involvement of ERK1/2 pathway, while the latter, but not Fos, involves the intracellular event in VP neurons activated by IL-1beta . A single injection of recombinant mouse IL-2 (rmIL-2) caused a significant increase in VP and OT mRNA levels in the hypothalamus of nude mice. This effect was specific to the nude mouse . IL-2 released VP from the hypothalamus and amygdala of rats in vitro. The IL-2-and acetylcholine-induced VP release was antagonized by Ng-methyl-L-arginine, indicating a role for NO in this VP release . IL-2 caused a dose-dependent stimulation of VP, but not CRH, secretion from both the intact rat hypothalamus in vitro and hypothalamic cell cultures .
The activation of VP neurons in response to immune stimulation was mimicked by an intraperitoneal injection of lipopolysaccharide (LPS) in male Wistar rats. LPS treatment concomitantly decreased diuresis and increased plasma VP as well as VP neuron activity in vivo, and these effects occurred as early as 30 min. Activation was sustained for more than 6 h. Prostaglandin E2 (PG-E2), IL-1beta, and TNF-alpha mRNA expression were raised 3 h after LPS, whereas IL-6 mRNA level increased 30 min post-LPS. In vivo, electrophysiological recordings showed that brain IL-6 injection increased VP neuron activity similarly to peripheral LPS treatment .
Aged rats displayed a heightened, shorter lasting activation of VP neurons following LPS as compared to adults. IL-6 mRNA was 3-fold higher, while IGF-I mRNA was 10-fold lower in aged than in adult rats. Brain pre-treatment with neutralizing anti-IL-6 antibodies or recombinant IGF-I in aged rats reversed LPS-induced anti-diuresis . Centrally administered leukemia inhibitory factor (LIF) significantly increased the plasma VP concentration from 5 to 60 min after the injection . Cytokine induced CRF (CRH) and VP synthesis and/or release is modulated by CAT, prostaglandins (PGs), and nitric oxide (NO) .
Human peripheral blood mononuclear cells, predominantly B-cells and macrophages, possessed a homogeneous population of V1-like VP binding sites .
Effects on the central nervous system
VP attenuated significantly the febrile response of rabbits to bacterial pyrogen. As the body temperature rose in response to the pyrogen, the level of VP in the perfusate collected from the septal area decreased . Nude mice have an increased vasopressinergic function .
V1 vasopressin receptor agonist (V1 agonist) induces a complex intracellular Ca2+-signaling cascade in cortical astrocytes. V1 agonist dramatically decreased the mRNA level of five cytokines. IL-1beta and TNF-alpha expression was confirmed with reverse transcriptase-PCR. IL-1beta and TNF-alpha secretion was also decreased in response to V1 agonist . In rats the i.c.v. administration of VP suppressed the proliferative response of splenic T cells and NK cytotoxicity in an adrenal-independent manner. These effects were completely reversed by i.c.v. pre-administration of the V1 receptor antagonist .
Effect on the pituitary
The ACTH response to exogenous administration of VP was impaired in V1bR-/- mice, while CRH-stimulated ACTH release in V1bR-/- mice was not significantly different from that in the V1bR+/+ mice. VP-induced ACTH release from primary cultured pituitary cells in V1bR-/- mice was also blunted. The increase in ACTH after a forced swim stress was significantly suppressed in V1bR-/- mice .
In conscious male rats i.c.v. infusion of histamine (HA) stimulated PRL secretion. Pretreatment with a specific antiserum to VP, or a VP antagonist inhibited the PRL response to HA and inhibited the PRL response to restraint stress. In contrast, pretreatment with a specific oxytocin (OT) antagonist had no effect on the HA- or stress-induced PRL release . Vasopressin antiserum (VP-Ab) was administered i.v. to lactating rats 15 min before permitting their previously isolated pups to suckle or to continuously suckled rats. The suckling-induced rise in plasma PRL levels was significantly less in VP-Ab-treated mothers when compared to rats receiving a similar amount of normal rabbit serum (NRS) . Anterior pituitary cells derived from juvenile female turkeys were incubated with posterior pituitary extracts or test substances for 3 hr. Posterior pituitary extracts contained a potent substance(s) which stimulated PRL release in a concentration-dependent manner. VP and vasoactive intestinal peptide (VIP) antisera completely abolished the PRL-releasing activities of their respective peptides .
CRH, VP, ACTH and beta-endorphin (beta-END) are released in response to histamine and restraint stress. Pretreatment with CRH antiserum abolished the ACTH response to stress and inhibited the beta-END response by 60%. Immunoneutralization with VP antiserum had only half the inhibitory effect of that seen with CRH antiserum. CRH (100 pmol i.v.) increased the plasma levels of ACTH and beta-ENDir. This effect was abolished by pretreatment with CRH antiserum, whereas pretreatment with VP antiserum prevented the CRH-induced ACTH release and inhibited the beta-ENDir response by 50%. VP (24-800 pmol i.v.) stimulated ACTH and beta-ENDir in a dose-dependent manner. CRH and VP antisera each prevented the effect of VP (800 pmol) on ACTH secretion, whereas the beta-ENDir response to VP was only inhibited by about 60% by the antisera .
Endogenous oxytocin play a role in the control of basal GH release probably by stimulating somatostatin secretion and/or inhibiting GH-releasing hormone secretion or by both actions. Endogenous vasopressin and oxytocin play a physiologically significant stimulatory role in the control of basal ACTH release .
The novel high-affinity non-peptide CRH 1 receptor antagonist R121919 significantly inhibits stress-induced corticotropin release and displays anxiolytic effects in rats selectively bred for high anxiety-related behavior. R121919 attenuates the stress-induced release of corticosterone, PRL, and OT. Moreover, the decrease in plasma testosterone following exposure to stress is abolished by R121919. Our data indicate that antagonism of CRH 1 receptors may prevent stress-associated endocrine alterations . In rats with paraventricular nucleus lesions LPS was able to activate the hypophysial-adrenal system in the absence of hypophysiotrophic neuropeptides of paraventricular origin .
Regulation of immune/inflammatory reactions
Brattleboro (DI) rats are homozygous for diabetes insipidus and lack vasopressin, and were derived from Long-Evans (LE) rats. In DI rats, NK cell activity was significantly higher than in LE rats. Vasopressin replacement normalized water intake in DI rats, but had no significant effect on NK cell activity. DI rats exhibited lower plasma corticosterone levels, which were not elevated by vasopressin replacement. The results suggest that the lack of vasopressin in DI rats elevates baseline NK cell activity, probably via mechanisms that are secondary to the vasopressin deficiency (e.g. lower corticosterone levels) . Morphofunctional immune disorders were revealed in vasopressin-deficient Brattleboro rats during ontogeny. Permanent decrease in the number of blood lymphocytes, increase in neutrophil count, reduced activity of macrophages, early involution of the thymus and spleen, and suppression of antibody production were observed .
In mice with the disruption of the vasopressin receptor 1a (VPR1a) gene a shift from IgM(high)/IgD(high) to the more mature IgM(low)/IgD(high) B cells, a significantly greater extent of splenic B cells proliferation in response to anti-IgM stimulation, and enhanced IgG1 and IgG2b production in response to immune challenge with T-dependent antigen were demonstrated. B-1 cells were increased in VPR1a(-/-) mice. T cell differentiation and activation were normal in VPR1a(-/-) mice .
The VP-binding nonapeptide has the sequence Thr-Met-Lys-Val-Leu-Thr-Gly-Ser-Pro (binding peptide). VP and its 6-amino acid N-terminus cyclic ring pressinoic acid (PA) are both capable of replacing the IL-2 requirement for IFN-gamma production by mouse splenic lymphocytes. VP-binding peptide specifically and reversibly blocks VP help in IFN-gamma production, but fails to block the helper signal of PA. Thus, the intact VP molecule and not just the N-terminal cyclic ring are important for interaction with the binding peptide [32, 33].
Vasopressin enhances the autologous mixed lymphocyte response. Enhanced proliferation appears to be a specific response that is influenced by arginine residues in position 8 of this nonapeptide . Our research indicates that vasopressin is the hypothalaminc regulator of adaptive immunocompetence and that it is capable of maintaining immune homeostasis. Vasopressin regulates both the HPA axis and also PRL, so it is capable of maintaining physiological conditions for adaptive immune function (Table 1).
Table 1. Vasopressin and immune function
NIL inhibits serum IgG and IgM antibody formation [35 36].
NIL inhibits intestinal IgA antibody formation .
NIL inhibits the Arthus reaction (immune complex induced) [not published].
NIL inhibits the contact sensitivity reaction to DNCB .
NIL inhibits EAE clinical score .
NIL inhibits ACTH and cortisone response to inflammation in EAE .NIL animals do not develop EAE, desmopressin restores disease activity [Quintanar Stephano et al., not published].
Abbreviations: NIL= neurointermediate pituitary lobectomy in rats; DNCB = dinitrochlorobenzene; EAE = experimental allergic encephalomyelitis in rats
VP and Disease
It is well known that syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is often associated with inflammatory disease, and cytokines produced at inflammatory foci are thought to stimulate VP release .
Thirteen patients with multiple sclerosis (MS) were studied at baseline and with provocative tests of HPA axis function (ovine CRH, VP, and ACTH stimulation). Compared to matched controls, patients with MS had significantly higher plasma cortisol levels at baseline. Despite these patients with MS showed normal, rather than blunted, plasma ACTH responses to ovine CRH. Patients showed a blunted ACTH responses to VP stimulation and normal cortisol responses to high and low dose of ACTH stimulation .
In Lewis rats IL-1 priming markedly suppressed the neurological symptoms of experimental allergic encephalomyelitis (EAE), without affecting the onset or duration of the disease. Measurement of VP and CRH in the external zone of the median eminence revealed that, as compared to Wistar rats, Lewis rats exhibit low VP but identical CRH, and that IL-1 priming increases (0.001) VP without affecting CRH stores, which is consistent with a shift to VP-dominated control of ACTH secretion as described in Wistar rats under conditions of HPA hyper(re)activity. IL-1 priming of Lewis rats attenuated the ACTH responses to an IL-1 challenge 11 days later, which may relate to an increase in resting corticosterone levels. There was no effect on immune reactivity. It is concluded that IL-1-induced elevation of resting corticosterone levels may influence the development of EAE .
Total contents of immunoreactive (ir)-CRH in the spleen and thymus were not altered following the induction of arthritis, although a significant decrease was observed in splenic extracts from arthritis rats (40.0 +/- 4.2 fmol/g tissue) compared to controls (69.5 +/- 8.4 fmol/g tissue). Low levels of VP were also detected in immune tissues, with contents significantly increased in spleens from arthritis animals (17.4 +/- 1.6 fmol/g tissue) compared to controls (10.6 +/- 1.9 fmol/g) but thymic contents of VP were not altered by arthritis (10.6 +/- 1.3 fmol/g) compared to controls (9.2 +/- 0.7 fmol/g) .
Plasma VP values were significantly higher during pneumonia than after recovery despite similar plasma sodium concentrations, both before and after water load. A positive correlation between plasma VP and minimum urine osmolality was found during pneumonia. Thus, impairment in renal water excretion appeared to be due to resetting of the VP osmostat and could not be attributed to any recognized nonosmotic stimulus for vasopressin secretion .
Vasopressin exerts a local anti-inflammatory effect on the lung through the VPR2 in a model of sepsis . The potent VPR2 receptor agonist deamino-8-D-arginine vasopressin (dDAVP,) in established and primary cultured collecting duct kidney cells inhibited Toll-like receptor 4-mediated nuclear factor kappa B activation and chemokine secretion in a VPR2-specific manner. In vivo infusion of dDAVP induced a marked fall in proinflammatory mediators and neutrophil recruitment, and a dramatic rise in the renal bacterial burden in mice inoculated with pathogenic E. coli. Administration of the VPR2 antagonist SR121463B to E. coli-infected mice stimulated both the local innate response and the antibacterial host defense .
The acute phase response
The direct application of LPS to the hypothalamus in vitro does not stimulate the release of the hypothalamic peptides controlling the HPA axis, CRH and VP. LPS alone decreased both CRH and VP secretion from the hypothalamus. However, when applied together with a nitric oxide synthase inhibitor, the inhibitory effect on CRH was lost. Conversely, co-administration with heme oxygenase inhibitors transformed the inhibition of VP to stimulation, while having no effect on the inhibition of CRH. Ferrous hemoglobin reversed the inhibition of VP, but did not lead to stimulation. It is therefore concluded that LPS may stimulate endogenous pathways that lead to the generation of NO, which in turn inhibits CRH. In addition, it generates carbon monoxide (CO), which modulates the release of VP. These gases are thus potential counter-regulatory controls to the activation of the HPA .
Inhibitors of phenylethanolamine-N-methyltransferase (PNMT), which are active either peripherally (SKF 29661) or both peripherally and centrally (SKF 64139), thus lowering epinephrine (EPI) synthesis, were studied. In adult male rats SKF 64139 pretreatment significantly (p < 0.05) enhanced basal medial basal hypothalamus (MBH) and basal median eminence (ME) VP contents. LPS administration significantly (p < 0.05) decreased MBH VP in control and SKF-29661-pretreated rats and diminished (p < 0.05 vs. basal values) ME VP in all groups .
In rats 3-4 hours following LPS injection (100 micrograms/kg, i.v.), CRF gene transcription was upregulated in the paraventricular nucleus (PVN). Transcripts of CRF receptors type A were present in the hypothalamus 6 h after LPS treatment. However, no alterations in cytoplasmic VP mRNA levels were noted in rats injected with LPS. Because the dose of LPS we used stimulates ACTH secretion within 30 min, our results suggest that systemic LPS acts first within the median eminence, where it stimulates peptidic nerve terminals .
LPS potently stimulated CRH and VP secretion into portal blood of the pituitary gland in alert, normally behaving ewes, and cortisol and progesterone into peripheral blood. Both CRH and VP generally rose and fell simultaneously, although the peak of the VP response was approximately 10-fold greater than that of CRH. This stimulation coincided with significant suppression of GnRH and LH pulsatile secretion in these same ewes and with the generation of fever .
In Holstein steers LPS increased body temperature, plasma ACTH and cortisol (p < 0.05). The abundance of anterior pituitary VPR3 mRNA was decreased at 2, 4, and 12 h following LPS administration (p < 0.05) and returned to basal by 24 h. A similar temporal regulation of pituitary CRFR1 mRNA (p < 0.05), but not pituitary pro-opiomelanocortin (POMC) mRNA, was observed following LPS administration. Similar down regulation of CRFR1 mRNA was not observed in other brain regions following LPS administration (cerebellum, hypothalamus) .
Most people develop febrile illness on numerous occasions during a lifetime. These febrile episodes normally subside and are followed by healing and return to health and to normal adaptive immunocompetence. By now we understand how the APR develops and what it is doing. However, we know little about the recovery phase. One would expect that in accord with the tight neuroendocrine regulation of APR, the recovery phase also would be regulated by neuroendocrine mechanisms. Some recent observations on the role of vasopressin in immune function and in APR appear to provide indications of the mechanism of recovery, termed as immunoreversion .
During chronic inflammatory conditions, such as adjuvant-induced arthritis of rats, CRH does not act as the major ACTH-releasing factor. This is also true for experimental allergic encephalomyelitis, eosinophilia myalgia syndrome, systemic lupus erythematosus, and leishmaniasis. During chronic inflammation VP takes over as the major regulator of the HPA axis [3, 49].
Chronic intermittent exposure to immobilization, insulin-induced hypoglycemia or psychological stress stimuli have been shown to increase the number of CRF cells containing VP and to increase the ratio of VP to CRF within the zona externa of the median eminence [50-53]. In chronically restrained rats exogenous VP but not CRF was found to increase plasma levels of both ACTH and corticosterone . Chronic inflammatory stress is associated with much larger stimulation of VP than other stress models. Activation of CRH does not appear to play a role under these conditions. However, only CRH can stimulate POMC transcription, not VP . VP has been less potent than CRF in producing ACTH release from rat pituitaries. The effect of VP on CRF mediated ACTH release is either synergistic or additive . Thus, VP stimulates the HPA axis, but it also stimulates PRL secretion [22, 23].
There is evidence to indicate that VP is the hypothalamic regulator of immune homeostasis (Table 1). VP regulates pituitary hormones and directly affects lymphocytes. Our investigations indicate that VP is required for the maintenance of adaptive immunocompetence. Growth and lactogenic hormones are responsible for the maintenance of thymus function and of the T cell dependent adaptive immune system . It is clear that VP has the capacity to stimulate both the HPA axis and PRL in a balanced fashion. This is in contrast with CRH, which stimulates the HPA axis only. In APR CRH is dominant because of its resistance to GC inhibition, whereas VP has a secondary role in HPA activation. However, during chronic inflammatory disease VP will take over the regulation of the HPA axis. Moreover, VP has the capacity to stimulate PRL synthesis, which is suppressed during APR. PRL is able to maintain the adaptive immune system and thus restores adaptive immunocompetence, which sets the stage for recovery and healing. On this basis one may conclude that vasopressin is the hypothalamic hormone that coordinates recovery and healing from disease .
I Berczi – Department of Immunology, Faculty of Medicine, the University of Manitoba, Winnipeg, MB R3E 0W3, Canada
AQ Stephano – Department of Physiology, Free University of Augascalientes, Augascalientes, Mexico
K Kovacs – Department of Pathology, St. Michael’s Hospital, University of Toronto, Toronto ON, Canada
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