Is Vasoactive Intestinal Peptide (VIP) Anti-Inflammatory?

Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells

Is Vasoactive Intestinal Peptide (VIP) Anti-Inflammatory?

  • PDF
  • Split View
    • Article contents
    • Figures & tables
    • Video
    • Audio
    • Supplementary Data

Objective.

Vasoactive intestinal peptide (VIP) has demonstrated beneficial effects in several murine models of immune-mediated inflammation by inhibiting both the inflammatory and the autoimmune components of the disease.

We investigate its potential to modulate the release of proinflammatory cytokines and chemokines by human synovial cells from patients with rheumatoid arthritis (RA).

Methods. Fresh suspensions of synovial tissue cells (STC) or cultured fibroblast- synoviocytes (FLS) were obtained from patients with RA or osteoarthritis (OA).

The effects of VIP on basal or tumour necrosis factor α (TNF-α)-stimulated production of CCL2 (MCP-1, monocyte chemotactic protein 1), CXCL8 [interleukin (IL)-8], IL-6 and TNF-α were studied by specific ELISAs (enzyme-linked immunosorbent assays).

The mRNAs for CCL2, CXCL8 and IL-6 in FLS were analysed by real-time reverse transcription–polymerase chain reaction.

Results. VIP at 10 nm down-regulated chemokine production by STC and FLS from RA and OA patients. VIP also down-regulated the expression of mRNAs for CCL2, CXCL8 and IL-6. The effects of VIP were more clearly detected in RA samples and after stimulation with TNF-α.

Conclusion. Our observations confirm that the proposed anti-inflammatory actions of VIP in murine models also apply to human synovial cells ex vivo. Further studies are encouraged to evaluate the use of VIP as a potential therapy for chronic inflammatory joint diseases.

VIP, Rheumatoid arthritis, CXCL8, CCL2, TNF-α, IL-6, Synoviocytes

Health depends on numerous regulatory interactions between the basic framework constituted by the three systems involved in homeostasis: the nervous, endocrine and immune systems. In chronic inflammatory diseases, disruption of neuroendocrine–immune interactions has been proposed [1, 2].

An important factor in these interactions is the existence in neural and immune cellular elements of common mediators, such as neuropeptides and their receptors, that can participate in the pathogenesis of chronic inflammation [3, 4]. Vasoactive intestinal peptide (VIP) is a neuropeptide that is detected in human serum in the picomolar range [5].

It is released by nerve fibres and lymphocytes in the lymphoid microenvironment and modulates innate and adaptive immunity through cellular signalling mediated by G protein-coupled receptors [6, 7].

In murine experimental disease models, modulation of this pathway has demonstrated a remarkable therapeutic effect in several inflammatory and autoimmune disorders, such as septic shock, TNBS (trinitrobenzene sulphonic acid)-induced colitis, and collagen-induced arthritis [8–10].

Chronic inflammatory rheumatic diseases, such as osteoarthritis (OA) and rheumatoid arthritis (RA), are characterized by the migration of leukocytes into the synovial tissue.

Leukocytes and resident cells produce various inflammatory mediators, including cytokines and matrix-degrading enzymes, that perpetuate chronic inflammation and tissue damage.

We have recently described the beneficial effects of VIP and its related peptide pituitary adenylate cyclase-activating polypeptide (PACAP) by inhibiting both the inflammatory and the autoimmune component in collagen-induced arthritis (CIA) [9, 11].

The local synthesis of proinflammatory cytokines by inflammatory cells, notably interleukin (IL)-1, IL-6 and tumour necrosis factor α (TNF-α), plays an important role in initiating and perpetuating inflammatory and destructive processes in the rheumatoid joint [12].

Chemokines released by resident synoviocytes are important effectors involved in the recruitment of neutrophils, monocytes and lymphocytes, and play an important role in inflammatory cell infiltration [13].

Although our previous data in murine CIA indicated that VIP inhibits both chemotactic and proinflammatory cytokines [9], its participation in human arthritis has not been elucidated and studies on the role of VIP as an anti-inflammatory agent in humans are scarce [14].

The aim of the present study was to evaluate in vitro the potential effects of VIP in the synthesis of chemotactic and proinflammatory cytokines by synovial cells from OA and RA patients.

Patients and tissue samples

Synovial tissue was obtained from six patients with RA and three patients with osteoarthritis (OA) at the time of knee prosthetic replacement surgery. All RA patients fulfilled the American College of Rheumatology 1997 criteria for the diagnosis of RA [15].

The study was performed according to the ethics recommendations of the Declaration of Helsinki and was approved by the Ethics Committee of Clinical Investigation of the Hospital 12 de Octubre. Fibroblast- synoviocyte (FLS) cultures were established from homogenized synovium in 10% FCS-DMEM (fetal calf serum–Dulbecco's Modified Eagle Medium) [16].

FLS cultures were used between passages 3 and 6. Freshly obtained total synovial tissue cells (STC) were also prepared from three patients with RA and three patients with OA by collagenase digestion of synovial tissue, and were maintained in RPMI medium (Life Technologies, Paisley, UK) [9].

FLS or STC were stimulated with 10 nm TNF-α (Genzyme, Cambridge, MA, UK) in the presence or absence of different concentrations of VIP (Neosystem, Strasbourg, France) for 24 h. Culture supernatants were harvested and stored at −20°C for determination by enzyme-linked immunosorbent assay (ELISA).

RNA was also obtained from FLS cultures (1 × 106 cells/ml) by using the Ultraspec RNA Isolation System (Biotecx Laboratories, Houston, TX, USA) according to the manufacturer's instructions. RNA was resuspended in DEPC (diethyl pyrocarbonate)-treated water and quantitated spectrophotometrically at 260/280 nm.

Cytokine determination: ELISA assay

The amounts of IL-6, TNF-α, CCL2 (MCP-1, monocyte chemotactic protein 1) and CXCL8 (IL-8) in the supernatants of cell cultures were determined with a human capture ELISA assay.

Briefly, a capture monoclonal anti-human IL-6, TNF-α, CCL2 or CXCL8 antibody (Pharmingen, Becton Dickinson Co, San Diego, CA, USA) was used to coat microtitre plates (ELISA plates; Corning Inc., New York, USA) at 2 μg/ml at 4°C for 16 h.

After washing and blocking with phosphate-buffered saline (PBS) containing 3% bovine serum albumin, culture supernatants were added to each well for 12 h at 4°C. Unbound material was washed off and a biotinylated monoclonal anti-human IL-6, TNF-α, CCL2 or CXCL8 antibody (Pharmingen) was added at 2 μg/ml for 45 min.

Bound antibody was detected by addition of avidin–peroxidase for 30 min followed by addition of the ABTS substrate solution (Sigma Chemicals Co., St Louis, MO, USA). Absorbances at 405 nm were taken 20 min after the addition of substrate.

A standard curve was constructed using various dilutions of human recombinant rIL-6, rTNF-α, rCCL2 or rCXCL8 in PBS containing 10% fetal bovine serum. The amounts of cytokines in the culture supernatants were determined by extrapolation of absorbances to the standard curve. The intra-assay and inter-assay variability for cytokine determination was

Source: https://academic.oup.com/rheumatology/article/43/4/416/1784552

Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation

Is Vasoactive Intestinal Peptide (VIP) Anti-Inflammatory?

Parkinson’s disease (PD) is a common neurodegenerative disorder with no effective treatment, characterized by a massive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In addition to other specific mechanisms, activated microglia cells, through the action of their derived cytotoxic factors, actively participate in the pathogenesis of PD.

The present study investigates the potential neuroprotective effect in a murine model of PD of the vasoactive intestinal peptide (VIP), a neuropeptide with a potent anti-inflammatory effect, which has been found to protect from other inflammatory disorders. The involvement of activated microglia and their derived cytotoxic products in such effect has been also investigated.

1. VIP protects from MPP+-induced dopaminergic neurodegeneration and microglia activation in vitro

To elucidate PD pathogenic factors, and thus to develop therapeutic strategies, a murine model was used.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces most of the clinical, biochemical, and neuropathological hallmarks of PD, including dramatic neurodegeneration of the nigrostriatal dopaminergic pathway.

We first investigated the in vitro effect of VIP on MPP+-induced neurodegeneration in ventral midbrain cultures. Treatment of mesencephalic cultures with MPP+ results in a dramatic decrease in the number of dopaminergic TH+ (tyrosine hydroxilase) neurons and in [3H]dopamine uptake.

The MPP+-induced dopaminergic cell loss was paralleled by an increase in the number of activated microglia and in TNF-α production. VIP prevented, in a dose-dependent manner, MPP+-induced TH+ neurodegeneration and microglia activation (not shown).

2. Neuroprotective effect of VIP on MPTP-induced nigrostriatal dopaminergic neuronal death in vivo

We next investigated the effect of VIP in the MPTP murine model of PD, where we determined dopaminergic neuronal cell loss in SNpc by counting TH+ neurons, 1 wk after administration of MPTP (Fig. 1⤻ A). The density of dopamine transporter (DAT, [3H]-mazindol) binding sites was used as an anatomical marker of nigrostriatal innervation (Fig. 1B⤻ ).

Levels of TH protein and catechols (dopamine and DOPAC) in striatum were determined as biochemical markers of dopaminergic nigrostriatal function (Fig. 1C-E⤻ ). The content of striatal nitrotyrosine was evaluated as a measure for the nitric oxide (NO) -related oxidative damage of the MPTP neurotoxic process (Fig. 1F⤻ ).

MPTP administration results in a dramatic decrease in the number of SNpc dopaminergic neurons, a loss of dopaminergic terminals in the striatum (Fig. 1A, B⤻ ), a decrease in striatal TH protein levels (Fig. 1C⤻ ), a depletion in dopamine and its major CNS metabolite DOPAC (Fig.

1D, E⤻ ), and an increase in the levels of striatal nitrotyrosine (a fingerprint of NO-derived modification of protein and one of the main markers of oxidative damage mediated by MPTP) (Fig. 1F⤻ ).

Stereotaxic administration of VIP into the left SN of MPTP-treated mice significantly prevented, in a dose-dependent manner, the ipsilateral SNpc dopaminergic neuronal cell death, the loss of striatal dopaminergic fibers, subsequent depletion of TH, dopamine and DOPAC, and the increase in nitrotyrosine levels (Fig. 1)⤻ .

The neuroprotective effect of VIP in the contralateral nigrostriatal system was much lower (not shown). Systemic administration of VIP (i.p. injection) was much less effective. Doses 15-fold higher were necessary for a significant effect, which was 50% less efficient than cerebral VIP administration (not shown).

Figure 1. Neuroprotective effect of VIP on MPTP-induced nigrostriatal dopaminergic neuronal death in vivo.

3. VIP prevents MPTP-induced microglia activation in vivo

In addition to the dramatic loss of dopaminergic neurons, PD is characterized by microglial activation in SNpc and striatum, and several studies have associated cytotoxic factors produced by activated microglia with the ongoing dopaminergic neurodegeneration.

Since VIP inhibition of microglia activation under inflammatory conditions has been described, VIP-mediated microglia deactivation emerges as a possible mechanism mediating the protective effect of VIP on MPTP-induced neurodegeneration. As shown in Fig.

2⤻ A, MPTP administration results in a dramatic increase in the number of activated microglia in both striatum and SNpc, as indicated by high expression of Mac-1, a specific marker for activated microglia, and the change in morphology (large cell body with poorly ramified short and thick processes) compared with saline-injected mice, which showed minimal microglial activation (low Mac-1 expression and small microglial cell body with thin and ramified processes). MPTP-induced microglial activation is paralleled by increases in TNF-α, IL-1β, and inducible NO synthase (iNOS) mRNA expression in striatum and SNpc (Fig. 2B⤻ ), which correlates with an augmentation in TNF-α and IL-1β protein levels and in iNOS activity in the ventral midbrain (Fig. 2C⤻ ). Double in situ hybridization and immunocytochemical examination showed that the majority of cells expressing these inflammatory mediators are microglia (Fig. 2B⤻ ). MPTP increased NADPH-oxidase activation, evidenced by translocation of the p67phox subunit from the cytosol to the plasma membrane (Fig. 2C⤻ ). iNOS and NADPH-oxidase are two prominent enzymes of activated microglia producing NO and reactive oxygen species (ROS), which together with TNF-α and IL-1β are well-known microglial-derived noxious mediators in neurodegeneration. VIP administration to MPTP-treated mice abolished all these events. VIP significantly reduced MPTP-induced microglia activation, expression of the neurotoxic factors TNF-α and IL-1β, and enzymatic activity of iNOS and NADPH-oxidase (Fig. 2)⤻ .

Figure 2. VIP prevents MPTP-induced microglia activation in vivo.

The involvement of astrocytes in the mediation of VIP, although minimal, should not be discounted, because VIP slightly reduced the MPTP-induced astrogliosis (not shown). Although it is unly that the reduction of MPTP-induced microglia activation by VIP is secondary to the attenuation of neuronal loss but rather the reverse, a direct action of VIP on neurons cannot be ruled out.

CONCLUSIONS AND SIGNIFICANCE

We propose that similar to after endotoxin-induced injury and brain trauma, in the MPTP murine model of PD and possibly PD itself, VIP, probably through the inhibition of proinflammatory noxious mediators (i.e.

, NO, ROS, TNF-α, and IL-1β) produced by activated resident microglia, prevents the loss of dopaminergic cells and nerve fibers in the nigrostriatal pathway.

Our study invites important future directions, including the possible therapeutic role of VIP in brain disorders such as multiple sclerosis, Alzheimer’s disease, and AIDS dementia, where inflammatory responses play a major role.

Since an inflammatory response is involved in PD, antioxidants or other newly developed, nonsteroidal anti-inflammatory drugs, such as iNOS inhibitors, cyclo-oxygenase inhibitors, or minocycline have been proposed for treatment in PD.

However, although several drugs offered neuroprotection in animal models, there has been little or no success in the clinical treatment of PD. This may indicate that the animal models do not reflect the events in PD or that neuronal cell death involves a cascade of events that cannot be prevented by a single neuroprotective drug. Thus, consideration should be given to multidrug therapy, similar to the approach taken in AIDS and cancer therapy. It is also possible that agents such as VIP that affect a large spectrum of inflammatory mediators might be at an advantage compared with other anti-inflammatory agents.

Figure 3. VIP prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinson’s disease by inhibiting microglia activation.

Source: https://www.fasebj.org/doi/abs/10.1096/fj.02-0799fje

Therapeutic Efficacy of Stable Analogues of Vasoactive Intestinal Peptide against Pathogens

Is Vasoactive Intestinal Peptide (VIP) Anti-Inflammatory?

  1. From the ‡Institute of Parasitology and Biomedicine, CSIC, Granada 18016, Spain,
  2. the §Department of Pathological Anatomy, Medical School of Granada, Granada 18012, Spain,
  3. the ¶Department of Molecular Microbiology, Washington University School of Medicine, St.

    Louis, Missouri 63110, and

  4. the ‖Department of Biochemistry and Molecular Biology, Medical School of Seville, Seville 41009, Spain
  1. ↵1 To whom correspondence should be addressed: Institute of Parasitology and Biomedicine, CSIC, Avd. Conocimiento, PT Ciencias de la Salud, Granada 18016, Spain. Tel.

    : 34-958-181670; Fax: 34-958-181632; E-mail: elenag{at}ipb.csic.es.

Background: Antimicrobial properties of the anti-inflammatory neuropeptide VIP are limited by its unstable nature.

Results: The VIP derivatives protected against polymicrobial sepsis and cutaneous leishmaniasis by selectively killing pathogens through membrane-disrupting mechanisms.

Conclusion: Modification of critical residues in the native VIP sequence generates stable peptides with potent antimicrobial activities in vitro and in vivo.

Significance: This work indicates a molecular rationale for designing new agents against drug-resistant infectious diseases.

Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide recently identified as a potential antimicrobial peptide. To overcome the metabolic limitations of VIP, we modified the native peptide sequence and generated two stable synthetic analogues (VIP51 and VIP51(6–30)) with better antimicrobial profiles.

Herein we investigate the effects of both VIP analogues on cell viability, membrane integrity, and ultrastructure of various bacterial strains and Leishmania species.

We found that the two VIP derivatives kill various non-pathogenic and pathogenic Gram-positive and Gram-negative bacteria as well as the parasite Leishmania major through a mechanism that depends on the interaction with certain components of the microbial surface, the formation of pores, and the disruption of the surface membrane.

The cytotoxicity of the VIP derivatives is specific for pathogens, because they do not affect the viability of mammalian cells. Docking simulations indicate that the chemical changes made in the analogues are critical to increase their antimicrobial activities.

Consequently, we found that the native VIP is less potent as an antibacterial and fails as a leishmanicidal. Noteworthy from a therapeutic point of view is that treatment with both derivatives increases the survival and reduces bacterial load and inflammation in mice with polymicrobial sepsis.

Moreover, treatment with VIP51(6–30) is very effective at reducing lesion size and parasite burden in a model of cutaneous leishmaniasis. These results indicate that the VIP analogues emerge as attractive alternatives for treating drug-resistant infectious diseases and provide key insights into a rational design of novel agents against these pathogens.

Footnotes

  • ↵* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 AI031078 (to S. M. B.). This work was also supported by Excellence Grants from Junta de Andalucia (P09/CTS-4705) (to E. G.-R.) and European Cost Action (BM0802) (to E. G.-R.).
  • ↵ This article contains supplemental Fig. S1 and Tables S1–S6.
  • Received February 24, 2014.
  • Revision received April 2, 2014.

Source: https://www.jbc.org/content/289/21/14583.short

Is Vasoactive Intestinal Peptide (VIP) Anti-Inflammatory?

Is Vasoactive Intestinal Peptide (VIP) Anti-Inflammatory?

Scientists are investigating whether chronic inflammation and autoimmune issues are linked to VIP. Find out what role it plays in different tissues in the body and whether certain natural factors can increase it.

Disclaimer: This post focuses on the science of inflammation, immunity, and other aspects of health in relation to VIP. It is solely informational. Talk to your healthcare provider if you suffer from inflammatory diseases and/or other health issues.

Definition

Vasoactive intestinal peptide or VIP is a hormone produced in many tissues, including the gut, pancreas, and suprachiasmatic nuclei (SCN) of the hypothalamus [1].

Decades ago, scientists discovered that VIP stimulates the heart to contract, causes vasodilation (hence its name), and lowers blood pressure. It also increases glycogen breakdown and relaxes the smooth muscle of the trachea, stomach, and gallbladder [1].

Additionally, VIP increases motility, muscle relaxation of the GI tract (lower esophageal sphincter, stomach, gallbladder). It stimulates the secretion of water, bicarbonate, and bile into the pancreatic juice, stimulates pepsinogen, and lowers stomach acid secretion (by gastrin) and inhibits the absorption of water from the intestines [1].

Neurotransmitters & Circadian Patterns

Aside from impacting digestion, heart health, and immunity, VIP seems to act as a neurotransmitter. It’s found throughout the brain, and it affects brain blood flow, melatonin, and the circadian rhythm [2].

Studies suggest that VIP is highest in the morning, which elevates cortisol to wake us up. This is also why cortisol levels are typically highest when we start our days and lowest in the night when we sleep. Its action is connected to other important wake-sleep chemicals in the body orexin and adenosine [3].

You’ve probably heard of the fight-or-flight and rest-or-digest nervous systems. They usually oppose each other and use norepinephrine and acetylcholine, respectively. Scientists think that VIP belongs to the third type of nervous activity, which is neither flight-or-flight nor rest-or-digest [4, 5].

The nerves VIP belongs to mostly act on the gut and pelvis areas, blood flow, muscle tone, and signaling in the brain [4, 5].

Researchers think that VIP may increase:

Caveats and Limitations

Many of the human studies listed in this section talk about associations, which means that a cause-and-effect relationship can’t be determined.

Some studies were done only on lab animals and their findings can’t be applied to humans.

1) Anti-Inflammatory

VIP is hypothesized to decrease most inflammatory cytokines. It appeared to have anti-inflammatory effects in mouse models of arthritis [8].

In patients with asthma, a loss of VIP from the lung nerve fibers was associated with more constricted airways [9].

VIP was also explored as a prognostic marker in another study. Patients with early arthritis who maintained low VIP levels over a two-year follow-up period did worse, despite receiving more intense treatment. Additional studies are needed to confirm these findings [10].

According to one unverified theory, VIP may be needed for immune tolerance. Scientists suspect that it suppresses Th1 immune responses and promotes Th2-type responses. They are investigating whether VIP [11, 12]:

  • Decreases TGF–b1 in macrophages [13].
  • Suppresses inflammatory cytokines such as TNF, IL-2, IL-4, IL-5, IL-6, IL-12, IL-17 and chemokines [14].
  • Increases anti-inflammatory IL-10 and promotes immune tolerant T regulatory (Treg) cells [14].
  • Inhibits TLR4 and MyD88 activation [15, 16].
  • Boosts the immune system. It seems to cooperate with proinflammatory mediators, such as TNF, to induce Dendritic Cell maturation at the site of inflammation [17]. VIP increased CCL5, which helps recruit T cells [18].

However, these mechanisms were only researched in cells and animals. Less is known about the anti-inflammatory effects of VIP on humans.

See this great image that summarizes the immune effects of VIP and MSH.

2) Immune Balance

VIP is hypothesized to help autoimmune/inflammatory diseases, including rheumatoid arthritis, ulcerative colitis, multiple sclerosis, Parkinson’s disease, Crohn’s disease, septic shock, uveoretinitis, and experimental models of brain inflammation. Proper clinical data are lacking, though [12].

On the other hand, blood levels of VIP were elevated in patients with eczema in one study [19].

3) Brain Health

Scientists are investigating whether VIP has neuroprotective properties. It may raise cellular resistance against oxidative stress and help neuronal survival, but more research is needed [20].

VIP injected in the hippocampus exerted an anti-anxiety effect in rats [21].

On the downside, VIP was increased in women with chronic migraines. This may be because VIP increases blood flow, and excessive blood flow in certain brain blood vessels is thought to underlie migraine attacks [22].

4) Infection

Researchers are exploring if VIP has antimicrobial, antibacterial, and antifungal properties [23].

In test tubes, VIP displayed antimicrobial activity against Streptococcus mutans, Lactobacillus acidophilus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. These findings can’t be applied to humans [24].

5) Diabetes

Mice without VIP have elevated blood glucose, insulin, and leptin levels. They have enhanced taste preference for sweet foods, which is linked with leptin resistance due to abnormal taste buds [25].

6) Fertility

Some scientists think that VIP may be important for fertility. Human studies have not yet verified this. Released from the SCN in the brain, VIP increased the release of Gonadotropin Releasing Hormone (GnRH) in animals [26].

Female mice deficient in VIP produced about half the offspring of their normal sister mice even when mated to the same males in one experiment [27].

In another animal study, VIP-deficient female mice had a disrupted estrous cycle [27].

According to one unconfirmed theory, a lack of VIP may impair reproductive health by disrupting the circadian rhythm [27].

7) Sexual Health

In male animals, VIP helps induce penile erections [28].

VIP also helped scientists better understand the vaginal changes of arousal. VIP is thought to be responsible for increasing and maintaining vaginal lubrication in women, doubling the total volume of lubrication produced [7, 29].

8) Circadian Rhythms

Little is known about the effects of VIP on the circadian rhythm in humans. animal experiments, VIP is thought to be involved in synchronizing the timing of SCN function with the environmental light-dark cycle. Therefore, it might play a role in sleep [7].

VIP-deficient mice have less strong (i.e lower amplitude) circadian rhythms as well as sync clocks with the SCN and other tissue [27].

In the adrenals, circadian rhythms (Per1) were lost in VIP-deficient mice, while in the liver, the most dramatic impact was on the phase or timing of the rhythm [27].

9) Obesity

The effects of VIP on weight are mixed effects. On the whole, it’s thought to contribute to obesity more than to weight loss, but this hasn’t been confirmed. Studies suggest that VIP may have the following effects:

  • Inhibits appetite (via a-MSH or CRH pathways) [30].
  • Decreases basal metabolic rates [30].
  • Stimulates insulin secretion [31].
  • Lowers physical activity [30].

More human data are needed.

Cancer Research

The impact of VIP on cancer in humans is still poorly understood.

On the one hand, VIP is thought to combat inflammation and autoimmunity. On the other hand, it might work as a growth factor. Cell-based studies suggest that it may have proangiogenic functions in breast and prostate cancer, which would theoretically help tumors grow blood vessels and spread. This hasn’t been tested in humans [32].

Scientists are also exploring whether VIP increases VEGF and other pathways that induce tumor growth (EGFR and HER2 activation) and cancer genes (c-fos, c-jun, and c-myc oncogenes). Some evidence has linked VIP with the pathogenesis of prostate cancer. In prostate cancer cells, VIP stimulated prostate-specific antigen (PSA) secretion [32].

In one study, VIP suppression was suggested as protective against breast and prostate cancers. More human research is needed [32].

Precautions

You may try the complementary approaches listed below if you and your doctor determine that they could be appropriate.

Remember that none of them should ever be done in place of what your doctor recommends or prescribes.

Research Limitations

The impact of increasing VIP on human health is not well understood.

Plus, many of the factors listed below were researched only in animals and can’t be applied to humans.

Remember, increasing VIP is not always beneficial. The fact that the addictive compound nicotine increases VIP adds to this fact [33, 34, 35].

Intranasal VIP

The use of intranasal VIP is highly controversial. It’s known to be popular among doctors who claim to treat mold illness and CIRS. They claim VIP is often low in mold illness/CIRS, but this remains unproven.

CIRS itself is a controversial term, considered by most experts as a misleading and incorrect diagnosis.

In line with this, there are no approved treatments in the U.S. for CIRS.

Additionally, the FDA concluded that there are insufficient data to determine the safety of VIP for human use in chronic conditions.

The FDA is currently reviewing the status of VIP as a “bulk compound.”

Nonetheless, compounding pharmacies are still allowed to it. That means that, for now, it’s available as a compounded nasal spray with a doctor’s prescription.

1) Glycine

Glycine increased VIP by 3.2X in the daytime, which modulates the circadian rhythm [36].

Bone broth has glycine, but I prefer the supplemental form. Bone broth and chicken soup make me sleepy.

2) Vagus Nerve Stimulation

Stimulating the vagus nerve increased VIP in animals [37].

See our post on factors that may stimulate the vagus nerve.

4) Fasting

In an old study of 6 young men, fasting for 59 hours increased VIP from 3.6 to 10.2 pmol.1(-1) [38].

5) L-Arginine

L-Arginine supplementation increased VIP in the rat small intestine [39].

6) Lemon and Limonene

Lemon and limonene increased VIP in gut tissue in animals [40].

Other:

The following factors are theoretical. They help scientists better understand biochemical pathways, but their health impact hasn’t been tested in humans.

Anecdotally, people use ginger to increase VIP, but this isn’t backed by science.

Exercise and VIP

In healthy people, exercise seems to increase VIP [45].

In another study that included men with prostate cancer and athletes, exercise increased anti-VIP antibodies and suppressed VIP. This was seen as protective against prostate cancer [32].

Additionally, regular exercise is great for overall health. It improves blood flow, supports mood balance, and reduces inflammation in the long term [46].

Unless your doctor specifically advised against exercise, getting some moderate physical activity in your daily routine is always a good idea.

VIP Blood Levels

Lab results are commonly shown as a set of values known as a “reference range”, which is sometimes referred to as a “normal range”. A reference range includes the upper and lower limits of a lab test a group of otherwise healthy people.

Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.

VIP blood levels are usually only checked in people suspected to have with VIPomas, which are VIP-secreting tumors.

The normal range of VIP is 0-59 pg/mL, which may vary between labs [47, 48].

VIP levels are much higher in people with VIPomas.

Although some doctors order VIP blood tests for people they suspect have CIRS, evidence is completely lacking to support this practice.

Some lab-to-lab variability occurs due to differences in equipment, techniques, and chemicals used. Don’t panic if your result is slightly range – as long as it’s in the normal range the laboratory that did the testing, your value is normal.

However, it’s important to remember that a normal test doesn’t mean a particular medical condition is absent. Your doctor will interpret your results in conjunction with your medical history and other test results.

Have in mind that a single test isn’t enough to make a diagnosis. Your doctor will interpret this test, taking into account your medical history and other tests. A result that is slightly low/high may not be of medical significance, as this test often varies from day to day and from person to person.

Source: https://selfhacked.com/blog/vip-a-potent-anti-inflammatory-hormone-and-natural-ways-to-increase-it/

Role of vasoactive intestinal peptide in osteoarthritis

Is Vasoactive Intestinal Peptide (VIP) Anti-Inflammatory?

  1. 1.

    Umetsu Y, Tenno T, Goda N, Shirakawa M, Ikegami T, Hiroaki H. Structural difference of vasoactive intestinal peptide in two distinct membrane mimicking environments. Biochim Biophys Acta. 1814;2011:724–30.

  2. 2.

    Jiang W, Gao SG, Chen XG, Xu XC, Xu M, Luo W, et al. Expression of synovial fluid and articular cartilage VIP in human osteoarthritic knee: a new indicator of disease severity? Clin Biochem. 2012;45:1607–12.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  3. 3.

    Buljevic S, Detel D, Pucar LB, Mihelic R, Madarevic T, Sestan B, et al. Levels of dipeptidyl peptidase IV/CD26 substrates neuropeptide Y and vasoactive intestinal peptide in rheumatoid arthritis patients. Rheumatol Int. 2013;33:2867–74.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  4. 4.

    Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev. 2004;56:249–90.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  5. 5.

    Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids. 2013;45:25–39.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  6. 6.

    Gutierrez-Cañas I, Juarranz MG, Santiago B, Arranz A, Martinez C, Galindo M, et al. VIP down-regulates TLR4 expression and TLR4-mediated chemokine production in human rheumatoid synovial fibroblasts. Rheumatology. 2006;45:527–32.

    • Article
    • PubMed
    • Google Scholar
  7. 7.

    Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide prevents experimental arthritis by down-regulating both autoimmune and inflammatory components of the disease. Nat Med. 2001;7:563–8.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  8. 8.

    Sutton S, Clutterbuck A, Harris P, Gent T, Freeman S, Foster N, et al. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet J. 2009;179:10–24.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  9. 9.

    Schuelert N, McDougall JJ. Electrophysiological evidence that the vasoactive intestinal peptide receptor antagonist VIP6-28 reduces nociception in an animal model of osteoarthritis. Osteoarthritis cartilage. 2006;14:1155–62.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  10. 10.

    Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2013;21:16–21.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  11. 11.

    Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med. 2010;26:355–69.

    • Article
    • PubMed
    • PubMed Central
    • Google Scholar
  12. 12.

    Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386:376–87.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  13. 13.

    Brandt KD, Dieppe P, Radin E. Etiopathogenesis of osteoarthritis. Med Clin North Am. 2009;93:1–24. xv.

    • Article
    • PubMed
    • Google Scholar
  14. 14.

    McDougall JJ. Arthritis and Pain. Neurogenic origin of joint pain. Arthritis Res Ther. 2006;8:220.

    • Article
    • PubMed
    • PubMed Central
    • Google Scholar
  15. 15.

    McDougall JJ. Pain and OA. J Musculoskelet Neuronal Interact. 2006;6:385–6.

  16. 16.

    Niissalo S, Hukkanen M, Imai S, Törnwall J, Konttinen YT. Neuropeptides in experimental and degenerative arthritis. Ann N Y Acad Sci. 2002;966:384–99.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  17. 17.

    Juarranz Y, Gutierrez-Canas I, Santiago B, Carrion M, Pablos JL, Gomariz RP. Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts. Arthritis Rheum. 2008;58:1086–95.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  18. 18.

    Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001;49:27–37.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  19. 19.

    Tsukada T, Horovitch SJ, Montminy MR, Mandel G, Goodman RH. Structure of the human vasoactive intestinal polypeptide gene. DNA. 1985;4:293–300.

  20. 20.

    Gomariz RP, Juarranz Y, Abad C, Arranz A, Leceta J, Martinez C. VIP-PACAP system in immunity: new insights for multitarget therapy. Ann N Y Acad Sci. 2006;1070:51–74.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  21. 21.

    Abad C, Martinez C, Leceta J, Gomariz RP, Delgado M. Pituitary adenylate cyclase-activating polypeptide inhibits collagen-induced arthritis: an experimental immunomodulatory therapy. J Immunol. 2001;167:3182–9.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  22. 22.

    Chapman CR, Tuckett RP, Song CW. Pain and stress in a systems perspective: reciprocal neural, endocrine, and immune interactions. J Pain. 2008;9:122–45.

    • Article
    • PubMed
    • Google Scholar
  23. 23.

    Juarranz Y, Abad C, Martinez C, Arranz A, Gutierrez-Cañas I, Rosignoli F, et al. Protective effect of vasoactive intestinal peptide on bone destruction in the collagen-induced arthritis model of rheumatoid arthritis. Arthritis Res Ther. 2005;7:1034–45.

  24. 24.

    Carrión M, Juarranz Y, Seoane IV, Martínez C, González-Álvaro I, Pablos JL, et al. VIP modulates IL-22R1 expression and prevents the contribution of rheumatoid synovial fibroblasts to IL-22-mediated joint destruction. J Mol Neurosci. 2014;52:10–7.

    • Article
    • PubMed
    • Google Scholar
  25. 25.

    Hill CL, Gale DG, Chaisson CE, Skinner K, Kazis L, Gale ME, et al. Knee effusions, popliteal cysts, and synovial thickening: association with knee pain in osteoarthritis. J Rheumatol. 2001;28:1330–7.

  26. 26.

    von Rechenberg B, McIlwraith CW, Akens MK, Frisbie DD, Leutenegger C, Auer JA. Spontaneous production of nitric oxide (NO), prostaglandin (PGE2) and neutral metalloproteinases (NMPs) in media of explant cultures of equine synovial membrane and articular cartilage from normal and osteoarthritic joints. Equine Vet J. 2000;32:140–50.

  27. 27.

    Arranz A, Gutiérrez-Cañas I, Carrión M, Juarranz Y, Pablos JL, Martínez C, et al. VIP reverses the expression profiling of TLR4-stimulated signaling pathway in rheumatoid arthritis synovial fibroblasts. Mol Immunol. 2008;45:3065–73.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  28. 28.

    Foster N, Cheetham J, Taylor JJ, Preshaw PM. VIP Inhibits Porphyromonas gingivalis LPS-induced immune responses in human monocytes. J Dent Res. 2005;84:999–1004.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  29. 29.

    Juarranz Y, Gutiérrez-Cañas I, Arranz A, Martínez C, Abad C, Leceta J, et al. VIP decreases TLR4 expression induced by LPS and TNF-alpha treatment in human synovial fibroblasts. Ann N Y Acad Sci. 2006;1070:359–64.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  30. 30.

    Ding W, Wagner JA, Granstein RD. CGRP, PACAP, and VIP modulate Langerhans cell function by inhibiting NF-kappaB activation. J Invest Dermatol. 2007;127:2357–67.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  31. 31.

    Carrión M, Juarranz Y, Pérez-García S, Jimeno R, Pablos JL, Gomariz RP, et al. RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: immune regulation by vasoactive intestinal peptide. Arthritis Rheum. 2011;63:1626–36.

    • Article
    • PubMed
    • Google Scholar
  32. 32.

    Juarranz MG, Santiago B, Torroba M, Gutierrez-Cañas I, Palao G, Galindo M, et al. Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells. Rheumatology (Oxford). 2004;43:416–22.

    • CAS
    • Article
    • Google Scholar
  33. 33.

    Carrión M, Pérez-García S, Jimeno R, Juarranz Y, González-Álvaro I, Pablos JL, et al. Inflammatory mediators alter interleukin-17 receptor, interleukin-12 and −23 expression in human osteoarthritic and rheumatoid arthritis synovial fibroblasts: immunomodulation by vasoactive intestinal Peptide. Neuroimmunomodulation. 2013;20:274–84.

    • Article
    • PubMed
    • Google Scholar
  34. 34.

    Perez Garcia S, Carrión M, Jimeno R, Ortiz AM, González-Álvaro I, Fernández J, et al. Urokinase plasminogen activator system in synovial fibroblasts from osteoarthritis patients: modulation by inflammatory mediators and neuropeptides. J Mol Neurosci. 2014;52:18–27.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  35. 35.

    Long DL, Willey JS, Loeser RF. Rac1 is required for matrix metalloproteinase 13 production by chondrocytes in response to fibronectin fragments. Arthritis Rheum. 2013;65:1561–8.

    • CAS
    • Article
    • PubMed
    • PubMed Central
    • Google Scholar
  36. 36.

    Little CB, Barai A, Burkhardt D, Smith SM, Fosang AJ, Werb Z, et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 2009;60:3723–33.

    • CAS
    • Article
    • PubMed
    • PubMed Central
    • Google Scholar
  37. 37.

    Hernanz A, Medina S, de Miguel E, Martín-Mola E. Effect of calcitonin gene-related peptide, neuropeptide Y, substance P, and vasoactive intestinal peptide on interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha production by peripheral whole blood cells from rheumatoid arthritis and osteoarthritis patients. Regul Pept. 2003;115:19–24.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  38. 38.

    Hunter DJ, McDougall JJ, Keefe FJ. The symptoms of osteoarthritis and the genesis of pain. Rheum Dis Clin North Am. 2008;34:623–43.

    • Article
    • PubMed
    • PubMed Central
    • Google Scholar
  39. 39.

    McDougall JJ, Barin AK, McDougall CM. Loss of vasomotor responsiveness to the mu-opioid receptor ligand endomorphin-1 in adjuvant monoarthritic rat knee joints. Am J Physiol Regul Integr Comp Physiol. 2004;286:R634–41.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  40. 40.

    McDougall JJ, Karimian SM, Ferrell WR. Prolonged alteration of vasoconstrictor and vasodilator responses in rat knee joints by adjuvant monoarthritis. Exp Physiol. 1995;80:349–57.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  41. 41.

    McDougall JJ, Barin AK. The role of joint nerves and mast cells in the alteration of vasoactive intestinal peptide (VIP) sensitivity during inflammation progression in rats. Br J Pharmacol. 2005;145:104–13.

    • CAS
    • Article
    • PubMed
    • PubMed Central
    • Google Scholar
  42. 42.

    Groneberg DA, Welker P, Fischer TC, Dinh QT, Grützkau A, Peiser C, et al. Down-regulation of vasoactive intestinal polypeptide receptor expression in atopic dermatitis. J Allergy Clin Immunol. 2003;111:1099–105.

    • CAS
    • Article
    • PubMed
    • Google Scholar
  43. 43.

    Cheng C, Gao S, Lei G. Association of osteopontin with osteoarthritis. Rheumatol Int. 2014;34:1627–31.

    • Article
    • PubMed
    • Google Scholar
  44. 44.

    Pérez-García S, Juarranz Y, Carrión M, Gutiérrez-Cañas I, Margioris A, Pablos JL, et al. Mapping the CRF-urocortins system in human osteoarthritic and rheumatoid synovial fibroblasts: effect of vasoactive intestinal peptide. J Cell Physiol. 2011;226:3261–9.

    • Article
    • PubMed
    • Google Scholar
  45. 45.

    McDougall JJ, Watkins L, Li Z. Vasoactive intestinal peptide (VIP) is a modulator of joint pain in a rat model of osteoarthritis. Pain. 2006;123:98–105.

    • CAS
    • Article
    • PubMed
    • Google Scholar

Source: https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-016-0280-1

healthyincandyland.com