Vasoactive Intestinal Peptide

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We previously reported that early arthritis (EA) patients with low vasoactive intestinal peptide (VIP) serum levels demonstrate a worse clinical disease course. In this study, we analysed whether variants in the VIP gene correlated with its serum levels and clinical EA parameters. The VIP gene was sequenced in patients with extremely high/low VIP levels, measured by enzyme immunoassay. Sixteen single nucleotide polymorphisms (SNPs) were differentially distributed between both groups, which were subsequently genotyped in two patients' sets. We observed that patients with rs688136 CC genotype showed higher VIP levels in both discovery (n = 91; p = 0.033) and validation populations (n = 131; p = 0.007). This effect was attenuated by the presence of minor alleles rs35643203 and rs12201140, which showed a clear trend towards low VIP level association (p = 0.118 and p = 0.049, respectively). Functional studies with miR-205-5p, which has a target site in the 3' UTR close to rs688136, revealed a miRNA-mediated regulatory mechanism explaining the higher VIP gene expression in homozygous patients. Moreover, patients with a rs688136 CC genotype and no minor alleles of the other polymorphisms required less treatment (p = 0.009). We concluded that the identification of polymorphisms associated with VIP serum levels would complement the clinical assessment of the disease severity in rheumatoid arthritis patients.
This publication used the human VIP EIA kit (EK-064-16) from Phoenix Pharmaceuticals to measure VIP concentration in human serum
Seoane IV, Martínez C, García-vicuña R, et al. Sci Rep. 2018;8(1):2035.

OBJECTIVE: Suitable biomarkers are essential for the design of therapeutic strategies in personalized medicine. Vasoactive intestinal peptide(VIP) has demonstrated immunomodulatory properties in autoimmune murine and ex vivo human models. Our aim was to study serum levelsof VIP during the follow-up of an early arthritis (EA) cohort and to analyze its value as a biomarker predicting severity and therapeutic requirements.
METHODS: Data from 91 patients on an EA register were analyzed (76% rheumatoid arthritis (RA), 24% undifferentiated arthritis, 73% women, and median age 54 years; median disease duration at entry, 5.4 months). We collected per protocol sociodemographic, clinical, and therapeutic data. VIP levels were determined by enzyme immunoassay in sera harvested from the 91 patients (353 visits; 3.9 visit/patient) and from 100 healthy controls. VIP values below the 25(th) percentile of those assessed in healthy population were considered low. To determine the effect of independent variables on VIP levels, we performed a longitudinal multivariate analysis nested by patient and visit. A multivariate ordered logistic regression was modeled to determine the effect of low VIP serum levels on disease activity at the end of follow-up.
RESULTS: VIP concentrations varied considerably across EA patients. Those fulfilling the criteria for RA had the lowest values in the whole sample, although no significant differences were observed compared with healthy donors. Disease activity, which was assessed using DAS28, inversely correlated with VIP levels. After a two-year follow-up, those patients with low baseline levels of VIP displayed higher disease activity and received more intensive treatment.
CONCLUSION: Patients who are unable to up-regulate VIP seem to have a worse clinical course despite receiving more intense treatment. Therefore, measurement of VIP levels may be suitable as a prognostic biomarker.
This publication used the human VIP EIA kit (EK-064-16) from Phoenix Pharmaceuticals to measure VIP concentration in human serum
Martínez C, Ortiz AM, Juarranz Y, et al. PLoS ONE. 2014;9(1):e85248.

We explored the relation between vasoactive intestinal peptide (VIP), CRTH2, and eosinophil recruitment. It is shown that CRTH2 expression by eosinophils from allergic rhinitis (AR) patients and eosinophil cell line (Eol-1 cells) was up-regulated by VIP treatment. This was functional and resulted in exaggerated migratory response of cells against PGD2. Nasal challenge of AR patients resulted in a significant increase of VIP contents in nasal secretion (ELISA), and the immunohistochemical studies of allergic nasal tissues showed significant expression of VIP in association with intense eosinophil recruitment. Biochemical assays showed that VIP-induced eosinophil chemotaxis from AR patients and Eol-1 cells was mediated through the CRTH2 receptor. Cell migration against VIP was sensitive to protein kinase C (PKC) and protein kinase A (PKA) inhibition but not to tyrosine kinase or p38 MAPK inhibition or calcium chelation. Western blot demonstrated a novel CRTH2-mediated cytosol-to-membrane translocation of PKC-ε, PKC-δ, and PKA-α, -γ, and -IIαreg in Eol-1 cells upon stimulation with VIP. Confocal images and FACS demonstrated a strong association and co-localization between VIP peptide and CRTH2 molecules. Further, VIP induced PGD2 secretion from eosinophils. Our results demonstrate the first evidence of association between VIP and CRTH2 in recruitingeosinophils.
This publication used the human VIP EIA kit (EK-064-16) from Phoenix Pharmaceuticals to measure VIP levels in collected nasal secretion.
El-shazly AE, Begon DY, Kustermans G, et al. J Biol Chem. 2013;288(2):1374-84.

Multiple sclerosis (MS) is a severe debilitating disorder characterized by progressive demyelination and axonal damage of the central nervous system (CNS). Current therapies for MS inhibit the immune response and demonstrate reasonable benefits if applied during the early phase of relapsing–remitting MS (RRMS) while there are no treatments for patients that progress neither to the chronic phase nor for the primary progressive form of the disease. In this manuscript, we have studied the therapeutic efficacy of a cell and gene therapy strategy for the treatment of a mouse model of chronic MS [myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)]. We used allogenic mesenchymal stem cells (MSCs) asa therapeutic tool and also as vehicle to deliver fully processed 3.3-kDa vasoactive intestinal peptide (VIP) to the peripheral immune organs and to the inflamed CNS. Intraperitoneal administrations of MSCs expressing VIP stopped progression and reduced symptoms when administered at peak of disease. The improvement in clinical score correlated with diminished peripheral T-cell responses against MOG as well as lower inflammation,lower demyelination, and higher neuronal integrity in the CNS. Interestingly, neither lentiviral vectors expressing VIP nor unmodified MSCs were therapeutic when administer at the peak of disease. The increased therapeutic effect of MSCs expressing VIP over unmodified MSCs requires the immunoregulatory and neuroprotective roles of both VIP and MSCs and the ability of the MSCs to migrate to peripheral lymph organs and the inflamed CNS.
This publication used the human VIP EIA kit (EK-064-16) from Phoenix Pharmaceuticals to measure VIP levels in secreted lyophilized fractions in the medium of mesenchymal stem cells.
Cobo M, Anderson P, Benabdellah K, et al. Cell Transplant. 2013;22(5):839-54.

Vasoactive intestinal peptide (VIP) is a neuropeptide released from the autonomic nerves exerting multiple antiinflammatory effects. The aim of the present study was to investigate the impact of severe sepsis and hemofiltration in two settings on plasma and tissue concentrations of VIP in a porcine model of sepsis. Thirty-two pigs were divided into 5 groups: 1) control group; 2) control group with conventional hemofiltration; 3) septic group; 4) septic group with conventional hemofiltration; 5) septic group with high-volume hemofiltration. Sepsis induced by faecal peritonitis continued for 22 hours. Hemofiltration was applied for the last 10 hours. Hemodynamic, inflammatory and oxidative stress parameters (heart rate, mean arterial pressure, cardiac output, systemic vascular resistance, plasma concentrations of tumor necrosis factor-alpha, interleukin-6, thiobarbituric acid reactive species, nitrate + nitrite, asymmetric dimethylarginine) and the systemic VIP concentrations were measured before faeces inoculation and at 12 and 22 hours of peritonitis. VIP tissue levels were determined in the left ventricle, mesenteric and coronary arteries. Sepsis induced significant increases in VIP concentrations in the plasma and mesenteric artery, but it decreased peptide levels in the coronary artery. Hemofiltration in both settings reduced concentrations of VIP in the mesenteric artery. In severe sepsis, VIP seems to be rapidly depleted from the coronary artery and, on the other hand, upregulated in the mesenteric artery. Hemofiltration in both settings has a tendency to drain away these upregulated tissue stores which could result in the limited secretory capacity of the peptide.
This publication used the human VIP RIA kit (RK-064-16) from Phoenix Pharmaceuticals to measure VIP levels in plasma.
Kuncová J, Chvojka J, Sýkora R, et al. Physiol Res. 2011;60(3):531-40.

Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liverischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients.
This publication used the human VIP peptide (064-16) from Phoenix Pharmaceuticals for bioactivity study.
Kuncová J, Chvojka J, Sýkora R, et al. Physiol Res. 2011;60(3):531-40.

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