Involvement Of Vasoactive Intestinal Peptide Research Articles

The pathogenic Th profile of human activated memory Th cells in early rheumatoid arthritis can be modulated by VIP.

Our aim is to study the behavior of memory Th cells (Th17, Th17/1, and Th1 profiles) from early rheumatoid arthritis (eRA) patients after their in vitro activation/expansion to provide information about its contribution to RA chronicity. Moreover, we analyzed the potential involvement of vasoactive intestinal peptide (VIP) as an endogenous healing mediator. CD4+CD45RO+ T cells from PBMCs of HD and eRA were activated/expanded in vitro in the presence/absence of VIP. FACS, ELISA, RT-PCR, and immunocytochemistry analyses were performed. An increase in CCR6+/RORC+ cells and in RORC-proliferating cells and a decrease in T-bet-proliferating cells and T-bet+/RORC+ cells were shown in eRA. mRNA expression of IL-17, IL-2, RORC, RORA, STAT3, and Tbx21 and protein secretion of IL-17, IFNγ, and GM-CSF were higher in eRA. VIP decreased the mRNA expression of IL-22, IL-2, STAT3, Tbx21, IL-12Rβ2, IL-23R, and IL-21R in HD and it decreased IL-21, IL-2, and STAT3 in eRA. VIP decreased IL-22 and GM-CSF secretion and increased IL-9 secretion in HD and it decreased IL-21 secretion in eRA. VPAC2/VPAC1 ratio expression was increased in eRA. All in all, memory Th cells from eRA patients show a greater proportion of Th17 cells with a pathogenic Th17 and Th17/1 profile compared to HD. VIP is able to modulate the pathogenic profile, mostly in HD. Our results are promising for therapy in the early stages of RA because they suggest that targeting molecules involved in the pathogenic Th17, Th17/1, and Th1 phenotypes and targeting VIP receptors could have a therapeutic effect modulating these subsets.Key messages Th17 cells are more important than Th1 in the contribution to pathogenesis in eRA patients.Pathogenic Th17 and Th17/1 profile are abundant in activated/expanded memory Th cells from eRA patients.VIP decreases the pathogenic Th17, Th1, and Th17/1 profiles, mainly in healthy donors.The expression of VIP receptors is reduced in eRA patients respect to healthy donors, whereas the ratio of VPAC2/VPAC1 expression is higher.

Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions

Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide/neurotransmitter, is widely distributed in both the central and peripheral nervous system. VIP is released by both neurons and immune cells. Various cell types, including immune cells, express VIP receptors. VIP has pleiotropic effects as a neurotransmitter, immune regulator, vasodilator and secretagogue. This review is focused on VIP production and effects on immune cells, VIP receptor signaling as related to immune functions, and the involvement of VIP in inflammatory and autoimmune disorders. The review addresses present clinical use of VIP and future therapeutic directions.

The vasoactive intestinal peptide-receptor system is involved in human glioblastoma cell migration

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor in adults. This cancer has an infiltrative nature and the median survival of patients is about one year. Vasoactive intestinal peptide (VIP) belongs to a structurally related family of polypeptides and is a major regulatory factor in the central and peripheral nervous systems. VIP regulates proliferation of astrocytes and of numerous cancer cell lines and modulates migration in prostatic and colonic cancer cell lines. Little is known about the involvement of VIP and its receptors (VIP-receptor system) in proliferation or migration of GBM cells. The effects of VIP, PACAP and of synthetic VIP antagonists were tested in two human GBM cell lines, M059K and M059J, established from two different parts of a single tumor. In these cells, the data revealed that the VIP-receptor system did not affect proliferation but controlled cell migration. Indeed, in M059K cells which express components of the VIP receptor system, the VIP receptor antagonists and a PACAP antibody enhanced migration. The VIP receptor antagonists increased generation of typical migration-associated processes: filopodia and lamellipodia, and activation of Rac1 and Cdc42 GTPases. Reciprocally, in M059J cells which poorly express the VIP-receptor system, treatments with the agonists VIP and PACAP resulted in decreased cell migration. Furthermore, the peptides appeared to act through a subclass of binding sites displaying an uncommon very high affinity for these ligands. Taken together, these observations suggest that components of the VIP-receptor system negatively regulate cell migration, thus showing potential anti-oncogenic properties.

Vasoactive intestinal peptide behaves as a pro‐metastatic factor in human prostate cancer cells

There is little known on the involvement of vasoactive intestinal peptide (VIP) in the metastatic cascade of human prostate cancer, that is, cell proliferation, cell-cell adhesion, extracellular-matrix degradation, and migration/invasion. Here we evaluated the expression of related biomarker proteins (cyclin D1, metalloproteinases MMP-2 and MMP-9, and E-cadherin) in human androgen-dependent (LNCaP) and independent (PC3) prostate cancer cells. Reverse transcriptase (RT)-polymerase chain reaction (PCR), gelatin zymography, Western blotting, confocal immunofluorescence microscopy, and assays on cell proliferation, adhesion, wound-healing, migration and random homing were performed. VIP increased cell proliferation and cyclin D1 expression whereas it decreased cell adhesion and E-cadherin expression in LNCaP and PC3 cells. VIP enhanced the gelatinolytic activity of MMP-2 and MMP-9. Semiquantitative RT-PCR assays showed that VIP stimulated mRNA levels of these MMPs and suppressed mRNA levels of its inhibitory protein RECK. VIP promoted cell invasion and migration, and the responses were faster according to the most aggressive status in cancer progression (androgen-independence). The involvement of nuclear factor-kappaB (NF-kappaB) was demonstrated since the anti-inflammatory agent curcumin blocked VIP effects on the above biomarkers in both cell lines. Taken together, these results and the presence of kappaB sites on gene promoter of cyclin D1, MMPs and, possibly, E-cadherin suggest that VIP may act as a cytokine in an early metastatic stage of human prostate cancer through the NF-kappaB/MMPs-RECK/E-cadherin system. Our findings may help to define novel targets and agents with potential usefulness in prostate cancer therapy.

Involvement of Vasoactive Intestinal Peptide on Insulin-Like Growth Factor I-Induced Proliferation of Rat Pituitary Lactotropes in Primary Culture: Evidence for an Autocrine and/or Paracrine Regulatory System

In previous studies we demonstrated that insulin-like growth factor I (IGF-I) induces pituitary vasoactive intestinal peptide (VIP) gene expression and secretion, and that IGF-I-induced prolactin (PRL) release is mediated by VIP. In this study, we investigate the mitotropic action of IGF-I and VIP on pituitary lactotropes, and their possible interplay in this effect. Cultured male rat pituitary cells were treated with rhIGF-I (10^–7M) and/or VIP (10^–7M) for 48 h. 5-Bromo-2′-deoxyuridine (BrdU) (10 µM) was added for labeling proliferation of pituitary cells. BrdU-labeling indices indicative of the proliferation rate of lactotropes were determined by double-labeling immunofluorescence staining for PRL and BrdU. Treatment with either IGF-I or VIP increased BrdU-labeling indices of lactotropes, but there was no further increase upon combined incubation with both factors, suggesting an interaction between the signal transduction pathways of IGF-I and VIP. VIP antiserum partially suppressed IGF-I-induced BrdU-labeling indices of lactotropes. We also investigated the intracellular signal transduction pathways in the action of IGF-I and VIP on the proliferation of lactotropes. Treatment of pituitary cells with an inhibitor of the mitogen-activated protein kinase (MAPK) pathway completely abolished IGF-I-induced lactotrope proliferation, whereas it partially suppressed VIP-induced BrdU-labeling indices. The protein kinase A (PKA) inhibitor, which abolished the mitogenic action of VIP, markedly suppressed IGF-I-induced lactotrope proliferation. These results indicate that both IGF-I and VIP stimulate lactotrope proliferation, and that IGF-I-induced lactotrope proliferation is partially mediated by VIP produced locally. Also, this study suggests that interactions between MAPK and cyclic adenosine 3′,5′-monophosphate-PKA signaling pathways are implicated in the lactotrope proliferation induced by IGF-I and VIP.

How is the motility of gastrointestinal sphincters modulated by acupmoxa?

Traditional Chinese medicine has been developing for more than 2500 years to prevent and treat diseases in Eastern cultures. Although acupmoxa (acupuncture and moxibustion) has been recommended by World Health Organization in treatment of 43 disorders, the exact mechanisms remain to be elucidated. Due to the development of spinal gate theory, the discovery of opioid receptors and the endogenous opioid that resulted in a better understanding of the mechanisms of acupuncture analgesia, acupuncture is now proved to be effective in pain relief. Previous studies have shown that nonadrenergic noncholinergic (NANC) neuron is regarded as the main source of neurally induced relaxation of gastrointestinal sphincters, including low esophageal sphincter (LES), the sphincter of Oddi (SO) and internal anal sphincter (IAS). The involvement of vasoactive intestinal peptide (VIP) and nitric oxide (NO) by NANC neurons has been documented to relax the above-mentioned sphincters. By using open-tip manometry in small animals, moxibustion can also be studied scientifically. Change of skin temperature on acupoints is postulated to be one of the therapeutic mechanisms for moxibustion. Application of local somatothermal stimulation (LSTS) on acupoints has been reported to induce an inhibitory response of SO in cats, rabbits and humans and to relax IAS in rabbits and humans. In these circumstances, the mechanism is speculated as a consequence of somato-visceral reflex through a heat-sensitive neural release of NO, which is temperature-dependent and stimulation site-specific. The electroacupuncture (EA)-induced SO motility changes are not inhibited by pretreatment with atropine, propranolol, phentolamine or naloxon, but are blocked by pretreatment with cholecystokinin (CCK) receptor antagonist, proglumide, and by injection of anti-CCK-8 antibody during EA with a dose-dependent relationship. The fact that an obvious elevation of plasma CCK level during EA stimulation on GB 24 and LR 14 acupoints suggests that EA causes a secretion of CCK which in turn affect biliary tract motility in rabbits and cats. Viscero-visceral reflex regulation is a normal physiological response. A growing body of evidence suggests acupuncture and moxibustion may regulate visceral function and modulate immune response through a “somato-visceral regulation” mechanism. Recent advance in the technology of functional magnetic resonance image analysis has made visualization of brain image possible at the same time when sensory stimulation is applied at body surface. The effectiveness of acupuncture treatment can be well demonstrated in vivo and the lineage between somato-visceral regulation and corresponding brain function can thus be elucidated. The incorporation of Western innovations into traditional Chinese medicine will make acupmoxa an evidence-based medicine, which can withstand rigorous assessment of its effect and mechanism.

Gender-specific apposition between vasoactive intestinal peptide-containing axons and gonadotrophin-releasing hormone-producing neurons in the rat

Light microscopic double labeling immunocytochemistry for vasoactive intestinal peptide (VIP) and gonadotrophin-releasing hormone (GnRH) was carried out on the hypothalami of male and female rats. It was found that the number of VIP boutons that terminate on GnRH neurons and the percentage of GnRH neurons contacted by VIP axons were higher in females than in males. This sexual dimorphic interaction of VIP fibers and GnRH neurons may indicate the involvement of VIP in the gender-specific regulation of gonadotrophin release in rats.

Involvement of vasoactive intestinal peptide in the transmission of light information to the suprachiasmatic nucleus

Involvement of vasoactive intestinal peptide in the transmission of light information to the suprachiasmatic nucleus

A possible involvement of VIP in feeding-induced secretion of ACTH and corticosterone in the Rat

For decades it has been known that brain/ gut peptides are released during the ingestion of a meal. Although a multitude of actions have been attributed to these peptides acting in the brain, including the release or inhibition of a variety of pituitary hormones, the actual physiological roles of these substances in the brain have not been confirmed. For the first time, we have demonstrated that feeding-induced hypothalamic-pituitary-adrenal (HPA) secretion may involve the brain/ gut peptide, vasoactive intestinal peptide (VIP), acting in the paraventricular nucleus (PVN) of the hypothalamus. The effects of 24 h fasting and refeeding on the release of plasma ACTH and CORT secretion in male rats were investigated. Blood samples were collected 5 min prior to PVN administration of saline or VIP antagonist, [Lsy 1,Pro 2,5, Arg 3,4,Tyr 6]-VIP and 30 min after refeeding. Plasma ACTH and CORT concentrations were significantly increased by 43 and 485%, respectively, by 30 min ingestion of food. Pretreatment with the VIP antagonist (0.75 and 1.5 nmol/rat) significantly reduced the food-induced ACTH response by 69 and 76% and the CORT response by 58 and 65%, respectively. There were no significant differences in food-intake among groups. These results suggest that one potential role of hypothalamic VIP may involve activation of hypothalamic-releasing factors to regulate ACTH and CORT levels during or after a meal.

Vagal control of guinea pig tracheal smooth muscle: lack of involvement of VIP or nitric oxide.

Contractions of the vagally innervated guinea pig tracheal tube preparation were induced by 1) stimulation of the preganglionic cervical vagus nerve (PGS), 2) activation of postganglionic intrinsic nerves by use of transmural stimulation (TMS) in the presence of hexamethonium, and 3) exogenous application of spasmogens, acetylcholine (ACh) and histamine. Contractions were recorded as increases in intraluminal pressure of the sealed Krebs-filled tube preparation. In the absence of basal tone, contractions induced by both PGS and TMS were monophasic. When the tone was raised with histamine (1 microM), the rapid contractions were followed by a slow relaxation during TMS but not during PGS. There was no evidence for any involvement of the putative inhibitory nonadrenergic noncholinergic neurotransmitters vasoactive intestinal peptide (VIP) and nitric oxide (NO) in the response to PGS, because neither the peptidase alpha-chymotrypsin nor the NO synthase inhibitor NG-nitro-L-arginine affected PGS-induced contractions. However, both alpha-chymotrypsin and NG-nitro-L-arginine facilitated contractions induced by TMS, suggesting that both VIP and NO are involved in responses to TMS. The facilitation of TMS-induced contractions by NG-nitro-L-arginine was unaffected by epithelium removal. Therefore, neither VIP nor NO appears to be released during PGS, but both are released during TMS, and the generation of NO during TMS is independent of the epithelium.

Interplay of VIP and nitric oxide in regulation of the descending relaxation phase of peristalsis

Involvement of vasoactive intestinal peptide (VIP) and nitric oxide (NO) in neurally induced relaxation was examined in smooth muscle from rat colon. Relaxation induced by field stimulation or radial stretch (i.e., descending relaxation phase of the peristaltic reflex) was accompanied by VIP release and NO production. NG-nitro-L-arginine (L-NNA) abolished NO production in both preparations but only partly inhibited VIP release (45 +/- 8% at 8 Hz and 59 +/- 10% at 10 g stretch) and relaxation (62 +/- 5% and 35 +/- 6%); the effect of L-NNA was reversed by L-arginine but not D-arginine. The pattern implied that NO production normally acts to enhance VIP release. In addition, VIP induced relaxation and stimulated NO production in muscle strips and isolated colonic muscle cells: L-NNA abolished NO production but only partly inhibited relaxation (58 +/- 6%); oxyhemoglobin had no effect. The effect of L-NNA on relaxation was reversed by L-arginine but not by D-arginine. The protein kinase A inhibitor (R)-p-adenosine 3',5'-cyclic phosphorothioate [(R)-p-cAMPS] and the protein kinase G inhibitor KT5823 inhibited VIP-induced relaxation by 76 +/- 5 and 35 +/- 4%, respectively; a combination of the two inhibitors abolished relaxation. (R)-p-cAMPS blocked the direct relaxant effect of VIP, whereas KT5823 blocked the indirect effect of VIP mediated by NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal androgenization increases vasoactive intestinal peptide levels in rat anterior pituitary: possible involvement of vasoactive intestinal peptide in the neonatal androgenization-induced hyperprolactinemia

Accumulating evidence suggests that vasoactive intestinal peptide (VIP) may be a physiological PRL-releasing factor. In the present study, we examined a possible involvement of VIP in the neonatal androgenization (NA)-induced hyperprolactinemia. Twenty-four hours after birth, newborn female rats were injected sc with 1,000 micrograms of testosterone (NA) or with oil vehicle only (control). Both groups were sacrificed at 8 weeks of age. Compared to controls, NA rats showed significantly higher plasma PRL levels (7.3 fold), anterior pituitary (AP) PRL content (2.1 fold) and plasma estradiol levels (2.1 fold). AP VIP content was extremely higher (61 fold) in NA rats than in controls. However, NA did not affect VIP content in the suprachiasmatic nucleus, paraventricular nucleus or median eminence. These results suggest that the NA-induced hyperprolactinemia may be mediated, at least in part, by paracrine and/or autocrine effects of the increased AP VIP on PRL secretion. However, since the potentiation by NA of the AP VIP content was extremely marked compared to those of the other parameters, the possibility was also raised that the increased AP VIP may be involved in other endocrine and/or nonendocrine events occurring in the AP.

Vasoactive intestinal polypeptide actions on the guinea pig intestinal mucosa during neural stimulation

Electrical stimulation of the mucosal innervation of the guinea pig ileum results in an increase in chloride secretion that is mediated in part by excitation of muscarinic cholinergic receptors on enterocytes. This study investigated the involvement of vasoactive intestinal peptide in the cholinergic and noncholinergic phases of the secretory response evoked by electrical stimulation of submucosal neurons in the guinea pig ileum. Flat sheets of ileum set up in Ussing flux chambers responded to exogenous vasoactive intestinal peptide by an increase in baseline short-circuit current which was reduced by furosemide and by vasoactive intestinal peptide antiserum. When submucosal neurons were electrically stimulated, a biphasic change in short-circuit current was evoked. Vasoactive intestinal peptide, forskolin, and isobutylmethylxanthine enhanced the cholinergic portion of the response, whereas the antiserum prevented or reduced the effects of the peptide but not of forskolin. In the presence of atropine to eliminate the cholinergically mediated response, vasoactive intestinal peptide reduced the noncholinergic phase of the response and its action was prevented by the antiserum. Vasoactive intestinal peptide enhanced the increase in short-circuit current evoked by the muscarinic agonist bethanechol. These results demonstrate that vasoactive intestinal peptide and other substances that stimulate secretion by increasing cyclic 3′,5′-adenosine monophosphate levels in enterocytes potentiate the calcium-dependent, cholinergic phase of the chloride secretory response evoked by neural stimulation of the guinea pig ileum. No evidence was found for vasoactive intestinal peptide as the mediator of the noncholinergic phase of the response.