TNF alpha and Chronic Disease.

TNF alpha is critical to most chronic illnesses.  Regulating its overexpression is critical – but we are designed to have some TNF alpha all the time, and a whole lot when we need it.  So we will need to find ways to determine its proper balance. I think we have that available to us in our proper use of biomarkers of inflammation.

In this graphic the researchers bring our attention to the important subject of sensitizing cells to the TNF effect.  I believe this is at the heart of the downward spiral of chronic illnesses.

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http://www.jpp.krakow.pl/journal/archive/08_07_s3/articles/08_article.html

 

IMMUNE REGULATION OF ALZHEIMER’S AND DIABETES

This link is to an important presentation by the researcher working on the Enbrel® protocol for and therapy for Alzheimer’s. TBI and Stroke.  It may be equally important in autism.  Please go to the link and click on the video and then listen to his talk. It is important to what I will be talking about in the next series of blogs  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2100099/

And this literature points to the very complex regulatory role of NF- kappa B.  It is influenced by TNF and also regulates TNF.

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“TNF-α is one of the most prominent pro-inflammatory cytokines significantly increased in AD and it plays a central role in initiating and regulating the cytokine cascade during inflammatory responses. For example, TNF-α increases the expression of adhesion
molecules on the vascular endothelium, which allows leukocytes and immune cells to infiltrate areas of tissue damage and infection.” (I. Granic et al. / NF-κB in Alzheimer’s Disease and Diabetes).

IMMUNE REGULATION OF VASCULAR DISEASE

This quote from Blood Journal illustrates the complexity of the immune regulation of vascular disease. “Atherosclerosis is an inflammatory disease of the arterial wall that carries an important socioeconomic burden. The severe clinical manifestations of atherosclerosis (myocardial infarction, stroke) are mainly due to the abrupt obstruction of the vessel lumen by a thrombus formed on the contact of a ruptured or eroded atherosclerotic plaque. The available data strongly suggest that immunoinflammatory–related mechanisms are the major determinants of plaque complications. Therefore, most of the important advances in the comprehension of the mechanisms of atherosclerosis have come from studies aimed at elucidating the critical components involved in the modulation of the immunoinflammatory balance within the plaque. However, despite the increasing knowledge regarding the role of inflammation in atherogenesis, the precise intracellular transduction pathways involved in this process remain largely unexplored.”  (http://bloodjournal.hematologylibrary.org/content/103/3/754.2.full)

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Over the next weeks I will be pulling the facts together so you can make better health decisions about all these chronic illnesses including Cancer and HIV and most neurological problems. 

About Dr Bradstreet
Dr Bradstreet is a graduate of the University of South Florida College of Medicine and received his residency training at Wilford Hall USAF Medical Center. He is a Fellow of the American Academy of Family Physicians. He is an Adjunct Professor at the Southwest College of Naturopathic Medicine in Arizona. He is extensively published in the peer-reviewed literature on subjects of autism, oxidative stress, mitochondrial disorders, virology, hyperbaric oxygen, and toxicology (especially heavy metal chelation). He is trained in the the isolation and use of stem cells.

10 Responses to TNF alpha and Chronic Disease.

  1. Natasa says:

    Please have a look at below – there is a great number of similar studies out there like that one, including in vivo and animal ones …

    What if chelators commonly used in autism are having similar effect, along the same lines? The benefits that we are seeing in kids with chelators could be for completely different reasons than removal of mercury etc…

    Iron chelation decreases human immunodeficiency virus-1 Tat potentiated tumor necrosis factor-induced NF-kappa B activation in Jurkat cells.

    TNF-alpha stimulates HIV-1 replication via activation of the transcription factor NF-kappa B. TNF-mediated activation of NF-kappa B is known to involve the intracellular formation of reactive oxygen intermediates (ROIs). We recently demonstrated that HIV-1 Tat protein potentiates TNF-induced NF-kappa B activation by downregulation of manganese-dependent superoxide dismutase (MnSOD), shifting the cellular redox state towards pro-oxidative conditions. This study shows that treatment of Jurkat cells with iron chelator deferoxamine (DFO) strongly decreases HIV-1 Tat-potentiated TNF-induced NF-kappa B activation but does not modify NF-kappa B activation by TNF-alpha. The ability of iron chelators to reduce Tat-potentiated TNF-induced NF-kappa B binding activity suggests that iron and intracellular hydroxyl radicals (OH.) are required for Tat effect. Moreover, we have shown that exogenously generated OH. markedly enhanced TNF-induced NF-kappa B activation in a dose-dependent manner while was not sufficient to trigger activation of NF-kappa B by itself. In addition, iron chelators had no effect either on MnSOD activity or on the decrease of this activity by Tat. Iron chelators had also no effect on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), but could elevate the GSH:GSSG ratio decreased by Tat protein. These observations suggest that the formation of intracellular OH. in the presence of iron ions play a major role in HIV-1 Tat enhancement of TNF-induced NF-kappa B activation and that iron chelation may protect Jurkat T cells, at least in part, against oxidative stress induced by Tat.

    Shatrov VA, Boelaert JR, Chouaib S, Dröge W, Lehmann V.
    CJF 94-11 INSERM Cytokines et Immunité Antitumorale, Institut Gustave-Roussy, Villejuif, France.
    Eur Cytokine Netw. 1997 Mar;8(1):37-43.

    • Natasa, this is a very interesting idea. Clearly Oxidative stress is a big deal and intrinsically linked to immune activation by microglia and astrocytes. “Iron chelators had also no effect on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), but could elevate the GSH:GSSG“. There seems to be a typo in this sentence. Can you check the source document. This would appear to be a contradictory statement. Thanks

      • Natasa says:

        Yes that does sound confusing, could be due to cumbersome translation from original or they could mean that chelators had no effects on gsh:gssg ratio in normal cells but did have an effect when that ratio was decreased by Tat protein: “Iron chelators had also no effect on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), but could elevate the GSH:GSSG ratio decreased by Tat protein”

      • Natasa says:

        Anti-HIV effect of iron chelators: different mechanisms involved.
        http://www.ncbi.nlm.nih.gov/pubmed/11166663

        “…Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease….”

        This describes a different mechanism but very interesting:

        Disintegration of retroviruses by chelating agents:
        http://www.ncbi.nlm.nih.gov/pubmed/6816193

      • For years we have used chelation therapy in autism and other disorders. For years I have known the metal issue was only a small piece of chelation benefit. Chelators are excellent free radical scavengers. Whether iron is directly or indirectly involved in any autism is unknown, but I think iron has an unlikely autism. Here is why. Children in the US and Europe are born (with rare exceptions) in a birth process which involves rapid cord clamping. This greatly reduces the iron infused by the more natural process where cord flow drops after the baby starts breathing. In addition the ferritin levels we measure on children with autism are generally low normal or below normal. How this plays a role in HIV in a practical way is interesting and promising.

      • Natasa says:

        Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection.

        … Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.
        http://www.ncbi.nlm.nih.gov/pubmed/10609953

      • Natasa says:

        Reactive oxygen species facilitate the in vitro and in vivo lipopolysaccharide-induced release of tumor necrosis factor.
        Secretion of TNF from mouse peritoneal macrophages exposed to LPS in vitro was enhanced in the presence of H2O2 or sodium periodate. Neither of these agents induced release of TNF in the absence of LPS. Both iron chelators and free radical scavengers inhibited this enhanced secretion of TNF … Pretreatment with the iron chelator, desferal, or the free radical scavenger, BHA, inhibited TNF release in these animals. … http://www.ncbi.nlm.nih.gov/pubmed/2745981

        Intracellular metal ion chelators inhibit TNFalpha-induced SP-1 activation and adhesion molecule expression in human aortic endothelial cells.
        … Our data suggest that intracellular, but not extracellular, transition metal ions mediate inflammatory cytokine-induced SP-1 activation and adhesion molecule expression in endothelial cells. http://www.ncbi.nlm.nih.gov/pubmed/12633744

      • Natasa says:

        Intracellular metal ion chelators inhibit TNFalpha-induced SP-1 activation and adhesion molecule expression in human aortic endothelial cells.

        … Our data suggest that intracellular, but not extracellular, transition metal ions mediate inflammatory cytokine-induced SP-1 activation and adhesion molecule expression in endothelial cells. http://www.ncbi.nlm.nih.gov/pubmed/12633744

  2. Natasa says:

    why is my comment posted five days ago still not going through?

  3. As far as I know all posts are up to date. I will check with the service provider and see if I need to upgrade the site memory.

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