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Prostaglandin D2 suppresses human NK cell function via signaling through D prostanoid receptor

Discussion in 'Other Health News and Research' started by nanonug, Nov 5, 2012.

  1. nanonug

    nanonug Senior Member

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    This one is for searcher. Not exactly about low NK cells, about low NK cells function instead.


    Prostaglandin D2 suppresses human NK cell function via signaling through D prostanoid receptor.

    Chen Y, Perussia B, Campbell KS.
    Source

    Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
    Abstract

    NK cells play critical roles in immune responses against tumors or virus infections by generating type 1 cytokine and cytotoxicity responses. In contrast, during type 2 dominant immune responses, such as allergic diseases, activities of NK cells are often impaired. These type 2 immune-mediated diseases have been reported to be closely associated with local production of PGD(2). PGD(2) is an eicosanoid primarily synthesized by mast cells and alveolar macrophages, and it functions through two major receptors, D prostanoid receptor (DP) and chemoattractant receptor-like molecule on the Th2 cell. Within the immune system, PGD(2) binding to DP generally leads to suppression of cellular functions. In the current study, we show that: 1) DP is expressed in human NK cells as detected by mRNA analysis and Western blot; 2) PGD(2) inhibits cytotoxicity, chemotaxis, and type 1 cytokine production of human NK cells via signaling through DP; 3) PGD(2) signaling via DP elevates intracellular cAMP levels and the inhibitory effects on NK cells are cAMP dependent; 4) PGD(2) binding to DP suppresses Ca(2+) mobilization triggered by the cross-linking of the activating receptor, CD16. Together, these data uncover a novel mechanism by which PGD(2) functions through DP to suppress type 1 and cytolytic functions of human NK cells, thus contributing to the promotion of a type 2 immune response.
    PMID: 17709490
    searcher likes this.
  2. searcher

    searcher

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    Oh, thanks! I hadn't logged in this week until today. This is a great paper. I would love it if this is the missing piece to the puzzle. I wish it were easier/cheaper to test NK cell function-- it would be really helpful to test it during mast cell treatment. My NK function was 7 LU, which is really low, but that was while I was more symptomatic.

    I think most researchers see the NK cells as being closer to the root of our problems, but it would be interesting if it were just another downstream symptom of mast cell dysfunction. It doesn't seem like treating NK cell dysfunction is a miracle, and the immunomodulators that increase NK cell function are also likely affecting mast cell function.

    One finding in the paper was that the NK cells aren't being killed, just inhibited. So that fits with the observation that we don't have low NK cell numbers, just function.
    merylg and nanonug like this.
  3. searcher

    searcher

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    As I think people have mentioned in other thread, I guess PGD2 blockers are being developed to combat baldness. Time for some balding CFSers to enter some clinical trials? :)
    camas likes this.
  4. alex3619

    alex3619 Senior Member

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    Interesting paper. My main aim since 1993 in self treatment has been moderation of series 2 prostaglandins. If the primary culprit is PGD2 then there may be specific strategies that emerge from the science. I will have to look into this at some point.

    http://europepmc.org/articles/PMC3123801/reload=0;jsessionid=IsImFNsKt53H4au4YGwN.6

    "Prostaglandin (PGD) D2 is an arachidonic acid metabolite that exerts a range of biological activities including vasodilatation, bronchoconstriction, and inhibition of platelet aggregation.1–4 Prostaglandin D2 (PGD2) is synthesized by the isomerization of prostaglandin H2 (PGH2) through the enzymatic activity of PGD synthase. Two types of PGD synthase have been identified: lipocalin-type PGD synthase and hematopoietic-type PGD synthase (H-PGDS).5,6 Although lipocalin-type PGD synthase is present in meningeal cells, epithelial cells of the choroid plexus, and oligodendrocytes in the brain, as well as being involved in the sleep-wake cycle,7 H-PGDS is principally expressed in hematopoietic cells, such as mast cells.8,9 On stimulation with antigens, mast cells rapidly secrete PGD2.10,11 In addition, recent studies indicate that a small population of Th2-type cells and dendritic cells (DCs) harbor H-PGDS, producing PGD2 in response to a variety of stimuli.12–14 "

    This fits my issues exactly. I have both circadian dysfunction and bronchoconstriction issues. What does not fit is thin blood ... or does it? This would imply easy bleeding. I don't get that, but I do have a pattern of microbruises on the tops of my feet.

    Please note that PGD2 has a probable anti-inflammatory role. Its possible its released as a result of excessive inflammation - or in other words is a secondary consequence.

    Bye, Alex
    merylg, nanonug and searcher like this.
  5. searcher

    searcher

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    Hi Alex- if you don't mind talking about it, what sort of techniques are you using to moderate series 2 prostaglandins?
    PGD2 does seem like a good potential culprit to go after. I know we talk about histamine a lot, but I find the other mast cell mediators more interesting since our symptoms are typically way more debilitating than those of usual allergy sufferers, who presumably also have high histamine levels. Admittedly, it is much easier to go after histamine since we can get anti-histamines OTC vs. entering clinical trials for treating asthma or baldness.
  6. nanonug

    nanonug Senior Member

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    If there is mast cell activation, which is my hypothesis for ME/CFS, then maybe it just gets released as part of the "package". Aspirin is a standard treatment for people with mast cell activation disorders. In my case, due to gastritis, I cannot take this kind of stuff. I am going to have to ask my doctor for celecoxib (celebrex).
  7. alex3619

    alex3619 Senior Member

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    Hi nanonug, be careful with Celebrex. Occasional use is OK, long term use could be very damaging. I have used Celebrex and Vioxx, they are similar drugs. Vioxx was better, but then that increased effectiveness made it more damaging. What is needed are drugs that modify specific prostaglandins, not all prostaglandins. Aspirin is a suicide inhibitor of cyclo-oxygenase. As a result it impairs wound healing. This is critical to gut integrity, which is why we get gut damage from aspirin. We need to be able to regulate the prostaglandins, not shut them down. So far nobody has fully succeeded at doing this that I am aware of, though I have dabbled with nutritional strategies for doing this for 19 years.
    merylg likes this.
  8. nanonug

    nanonug Senior Member

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    Oh, yeah, I am aware of this! However, if downregulation the activity of COX-2 is the only away to go about things, I won't have any problem taking my chances.
  9. camas

    camas Senior Member

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    Nanonug, Just happened upon this post on COX-2 inhibiting supplements and thought it might interest you. I'm giving Holy Basil a try after reading that it is an H2 blocker and mast cell stabilizer.

    When I had my NK cell function checked in the early '90s (20 long years ago...how depressing), I remember it being low. Have no idea what it would be now. I don't know if anyone even bothers checking anymore.
  10. nanonug

    nanonug Senior Member

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    Thanks, I'll keep that list in mind, particularly the holy basil. I have started Normast a couple of days ago and don't want to try too many things at the same time.
  11. Marco

    Marco Old blackguard

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    If you already have neuroinflammation, which I suspect many of us do, COX-2 inhibitors may not be such a good idea long-term :

    Paradox suggests reasons why COX-2 inhibitors hurt and help




    http://scienceblog.com/community/older/2005/7/200506211.shtml
  12. alex3619

    alex3619 Senior Member

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    PGD2 is also critical for sleep. I suspect but have yet to form a final opinion that it is required to initiate sleep. So a universal block (not targeted) of PGD2 might worsen sleep issues.
    merylg likes this.
  13. nanonug

    nanonug Senior Member

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    You appear to be working under the assumption that people with mast cell disorders have "normal" levels of Prostaglandin D2. In many cases, that is not the case. The idea is to bring the levels down to "healthy" levels. As I said before, if the way to do it is with COX-2 inhibitors, then I'll do it.
  14. alex3619

    alex3619 Senior Member

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    Hi nanonug, the problem with PGD2 and other eicosanoids is we have no way of defining normal in the conventional sense. The technology does not exist as it has an extremely short half life - for PGD2 that is only six seconds. We can define normal blood levels, but this is meaningless. These hormones are LOCAL, meaning they operate at distances of around a millimeter. To research this kind of hormone you have to take a biopsy and chemically halt the degradation of the hormone. You can then measure it and determine probable concentrations in that tissue.

    If we had chronic severe systemic elevated PGD2 we would all be dead so far as I can see. The problem with PGD2 is that it can be elevated locally in tissues where it is not required. Suppressing that means understanding why its elevated and stopping the process, not stopping PGD2 globally. The toxicity of PGD2 is dependent on tissues. In some parts of the body it is fine to elevate concentrations ... given that such elevations have a limited boundary ... beyond where they are supposed to be the concentrations would be very very low.

    So halting chronic elevated PGD2 means that in some tissues it will move toward normal, and in others it will become deficient. This is the eicosanoid trap I have been trying to figure out for 19 years now.

    Let me give you a reason why PGD2 is not elevated universally in our bodies. It triggers sleep, though I have yet to research this further than the basics. We would not be able to stay awake for more than minutes at a time. Now some of us have that in severe ME. So these might be candidates for systemic block of PGD2 synthesis though I still think it could be dangerous. An example of elevated PGD2 causing sleep is African Sleeping Sickness.

    Another thing that would happen with chronic universal PGD2 elevation is severe breathing difficulties. We would be having constant airway blockage. This is not survivable.

    However a patient who cannot stay awake and has such poor lung function that they cannot get much air in might find that COX-2 inhibitors are useful. This does require proper clinical trials though to be sure of the ramifications.

    Bye, Alex
  15. nanonug

    nanonug Senior Member

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    I recently did a 24-hour urinary Prostaglandin D2 test (Quest Diagnostics). A normal range is indeed defined. For more info, have a look at the document in the following post: Systemic Mast Cell Disease: An Update.
  16. alex3619

    alex3619 Senior Member

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    The problem with such tests is they give you a global average of highly degraded hormone concentrations. It says nothing about local concentrations. You could have very high PGD2 in some areas, and very low in others. Also, its very unlikely that it would reflect a correct measure of PGD2 in the brain. Not much brain PGD2 would survive to get into urine. To measure brain PGD2 even inaccurately you need spinal fluid.

    The PGD2 reflected in urine would be a very small percentage of actual concentrations. Those concentrations on a time point by time point basis would also vary a lot. They give a temporal average in the tests as well as a whole body average, and both are degraded from real concentrations. What you are getting mostly is a measure of PGD2 in the kidneys. However if they found a PGD2 degradation product that is stable, then they could use that to infer time and body averaged PGD2 concentrations - but it tells you nothing about spacial or temporal distribution, only that there is a problem. PGD2 has a marked circadian variation.

    Indeed its possible to have severe PGD2 excess or deficiency and have completely normal urine tests. Its also possible to have both severe excess and deficiency at the same time. This is part of the eicosanoid trap. If one tissue is chewing up arachidonic acid then others will be deficient.

    Bye, Alex
  17. nanonug

    nanonug Senior Member

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    Yes, but the purpose of such tests is to asses mast cell activation disorders. The reason I posted the study above was to potentially provide an explanation to the low NK cell function that (some) people with ME/CFS experience. It is within this context, that of ME/CFS being undiagnosed MCAS, that a global PGD2 makes sense due to aberrant mast cell activation. Once again, I invite you to have a lokk at the document in my previous post.
  18. alex3619

    alex3619 Senior Member

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    I have looked at the document. It does not change my analysis. PGD2 is strictly a local hormone. I have no doubt that it can be elevated locally. I have extreme doubt that it can be elevated globally and not put a patient into a coma and near death. It also cannot be sustained chronically elevated at a systemic level. This is all about local tissue elevations.

    For PGD2 to cause a massive systemic drop in NK cell function, it requires that the NK cells are all passing through a tissue in which PGD2 is elevated. This could be part of the liver or gut.

    Bye, Alex
  19. nanonug

    nanonug Senior Member

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    If this were true, serum and urinary PGD2 tests would make no sense. Given that they exist, and are used as diagnostic tools, I am strongly inclined to believe that your assertion of "strictly a local" is incorrect.
  20. nanonug

    nanonug Senior Member

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    Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE.

    1. R A Lewis,
    2. N A Soter,
    3. P T Diamond,
    4. K F Austen,
    5. J A Oates and
    6. L J Roberts 2nd
    Abstract

    Anti-IgE-dependent activation of rat and human mast cells resulted in the preferential generation of the cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin I2 (PGI2) in the rat and PGD2 in the human. The average net generation of PGD2, determined by gas chromatography-mass spectrometry, was 13.1 ng/10(6) purified rat mast cells and 39.5 ng/10(6) dispersed, enriched human mast cells. After IgE-dependent activation, there was a linear relationship between the net quantities of PGD2 generated and of histamine secreted from dispersed human pulmonary cells when the number of mast cells was varied but the total number of cells was held constant, indicating that it is the number of mast cells participating in IgE-dependent activation, rather than total mast cell number, that determines PGD2 generation. A linear relationship was also shown between PGD2 generation, determined by radioimmunoassay, and the release of the granule marker beta-hexosaminidase from purified rat mast cells on the dose-response portion of the plot of their response to anti-IgE challenge. With higher concentrations of anti-IgE, PGD2 generation from rat mast cells plateaued, whereas net percent beta-hexosaminidase release increased further. In kinetic studies of rat mast cells activated with anti-IgE, the onset (1 to 2 min) and time of maximum generation (5 to 10 min) for PGD2 were delayed relative to the onset (15 to 30 sec) and completion (1 to 2 min) of beta-hexosaminidase release. Thus, the extracellular appearance of PGD2 during IgE-dependent mast cell activation represents a response additional to the secretion of granule-associated mediators.
    • Copyright © 1982 by American Association of Immunologists

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