Study: Polymorphisms in Cytokines May Contribute to Autoimmune Disease in Canadian Aboriginal Populations~!

This has implications for conditions where methylation and polymorphisms that effect control of cytokines as well, including the Nrf2 pathway!


Larcombe, L. et al. Differential cytokine genotype frequencies among Canadian Aboriginal and Caucasian populations. Genes and Immunity 6, 140-144 (2004). URL http://dx.doi.org/10.1038/sj.gene.6364157.

Regulatory T cells activity is potentiated by glycogen synthase kinase 3beta inhibition.

Comment: It has been suggested that chemical sensitivity and other conditions related to other environmentally-induced syndromes are a consequence of "loss of tolerance" which may be attributed to a reduction in the production of regulatory T cells that can suppress autoimmune responses and also may help in glucose homeostatic regulation. GSK-3b is similar to the on/off switch for the antioxidant system and is upregulated in inflammatory conditions.  Insulin and exercise have been shown to inhibit GSK-3b and other studies report that inhibiting GSK-3b may also reduce Il-6.

"Inhibition of GSK-3beta leads to increased suppression activity by Tregs."

CiteULike: Suppressive Treg cell activity is potentiated by glycogen synthase kinase 3beta inhibition.:

Related: GSK-3b

Il-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats

"Orshal, J. M. and Khalil, R. A. (2004). Interleukin-6 impairs endothelium-dependent no-cgmp-mediated relaxation and enhances contraction in systemic vessels of pregnant rats. Am J Physiol Regul Integr Comp Physiol, 286(6):R1013-1023."


Read more: CiteULike: Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats:

Gulf War Syndrome, Chemical Sensitivity and Why Benefits of CPAP!

It has only been in the not-to-distant past that officials and medical experts have come out and admitted that Gulf War Syndrome is an actual disease and while many that have tried to find the cause the "true cause" is not yet known. In previous blogs, I have discussed how Gulf War Syndrome shares many of the same symptoms as other environmental conditions and are often co-morbid and include chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity and other environmental factors may contribute to fascilitate the condition that is commonly regarded as Gulf War Syndrome. One well-respected research blogger, Dr. Art Ayers, explains that CFS, MCS and fibromyalgia "can be induced by organophosphate pesticide exposure. In GWS, two insults seem to be needed: acetylcholine signal disruption and inflammation. He says that in the effected individuals the acetylcholine mimetics (pesticides, pyridostigmine) disrupted the nervous system and numerous immunological, infectious, chemical and emotional stresses generated a high level of chronic inflammation. The vaccine against anthrax and exposure to burning oil wells may have contributed to inflammation." Without a clear understanding of what causes GWS, physicians and health experts are mostly at a loss on how to treat it and clearly, most of the research is now focused on providing effective therapies until a cure is found for it.

In recent weeks, two interesting studies have been released that show CPAP (continuous positive airway pressure) may be beneficial in treating symptoms of Gulf War Syndrome with sleep disordered breathing. In the pilot study, findings demonstrated improvements in many symptoms including pain, fatigue, cognitive function, sleep quality, physical and mental health. The researchers' concluded from this experiment that CPAP can greatly improve overall health in GW patients with sleep disordered breathing which may be a distinguishing factor in veterans with GWI compared to veterans without Gulf War Illness. (Amin)  While this research is preliminary it provides interesting insight into GWS. Admittedly, there are reported side-effects associated with CPAP use and the pros and cons of it should be addressed fully with a qualified physician even if CPAP is taken out of the research lab and used as therapy for GWS.

To date, even with these published findings, the reader is left with the question why CPAP may be effective for treating some symptoms of GWS. The author only makes the comment that GWS experience a "frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation."  Taking a more holistic systematic approach to understanding the nature of GWS ; one can draw some conclusions that provide at least a reasonable explanation of what may be occurring in GW patients with sleep apneas and why CPAP may provide at least "some" relief. CPAP has been used for quite some time to  treat sleep apneas and more recently has been used for a variety of other medical respiratory conditions. Budhiraja explains that sleep disordered breathing is often associated with hypertension and that "sleep apnea, hypocapneas and hypoxemia contribute to alterations in sympathetic activity, changes in the renin-angiotensin pathway, impede xanthine oxireductase production, cause endothelial dysfunction and lower levels of eNOS."  If you are a consistent reader of my feeds, chronic low-level inflammation contributes to endothelial dysfunction and higher risk for cardiovascular disease in many environmentally-induced health conditions.

Recently, it has been suggested that sickness syndrome contributes to symptoms in GWS and may explain  fatigue, pain and other behavioral changes as well. Sickness syndrome is in associated with elevated levels of cytokines including Il-1b and Il-6 and these inflammatory cytokines may also be associated with PTSD and CFS and are activated during the general response to stress which can lead to changes in genetic expression. Two researchers, Burioka and Steiropoulis found significant changes in Il-6 and Tnf-a, uric acid and immune complexes after CPAP. These findings suggest intermittent hypoxia contibutes significantly to inflammation and noted positive changes in patients that use regularly CPAP .  We have suggested that insulin resistance may be a critical factor in environmental illness and obesity and dietary influences may influence the severity of many environmental diseases including sickness syndrome, PTSD, MCS, CFS and fibromyalgia. To some extent, this can be explained by the fact that inflammatory cytokines and adipokines such as leptin and adiponectin can produce systemic changes. Patients with OSA have a higher prevalence of insulin resistance both in the obese and non-obese. (Lam)

In severa studies, agents such as pesticides, particulates and compounds emitted from fires and other environmental conditions that GW veterans may have been exposed too, exert an inhibitory and/or negative influence on cell function. (Gulati) For example, the metabolites of many toxic chemicals consistent with these types of exposures bio-accumulate in adipose tissue and contribute to inflammation and insulin resistance. (Nov) More specifically, it is proposed immune-mediate macrophages in adipose tissue contribute to insulin resistance and Tregs dampen this response and their reduction may contribute to insulin resistance. (Winer) Also, smaller particulates that bind to metals and hydrocarbons and contain endotoxin may infiltrate deeply into body tissues and through a complex process, end up in vessels and contribute to inflammation that leads to vascular disease.  (Li) An August 2010 study of Gulf War patients demonstrate high prevalence of problems with hypercoagulation which are also common in sleep apnea patients and can potentially be reversed by use of CPAP in some individuals. (Guardiola, Nichols)

Sleep apnea often accompanies obesity and for years, it has been assumed that inflammation is an important consequence of obesity. However, many experts now believe endothelial inflammation probably precedes obesity. Whatever the case may be, CPAP has demonstrated therapeutic effects on inflammation in obesity and this inflammatory process is similar in other environmentally-induced diseases. This leads one to assume its benefits may be achieved in the same way for GWS patients. Budhiraja and others have shown,  "CPAP therapy improves endothelial function, decreases the abnormally increased levels of circulating apoptotic endothelial cells, attenuates free radical production from neutrophils and monocytes, reduces the levels of C-reactive protein (CRP), a marker of vascular inflammation, increases vasodilator levels and mediates a decline in vasoconstrictor levels  in patients with sleep apnea altering blood flow. In the future, more studies may demonstrate CPAP may be of benefit for other "somatic" environmental illnesses as well.  (Gold, El Soth) In CPAP studies in obese patients, CPAP therapy has shown to reduce oxidative stress as well as, raise levels of SOD and alter nitrate and nitrite levels. Other changes that are reflected during CPAP adjustments also may have positive influences on physiology in a so-far unknown way. (Calero)

I have agreed with a few health experts and proposed due to my own experiences with several environmental diseases, severe reactions of MCS may be caused by the "lack of tolerance" to environmental conditions. Reactions develops to conditions that were considered normal and therefore, is more like an autoimmune disease and inflammatory cytokines and epigenetic changes in gene expression are contributory to this disruption. This "loss of tolerance" could explain why MCS patients develop extreme sensitivity to very low levels of pollutants such as those found in perfumes and detergents. Chemical sensitivity is also common in Gulf War veterans but the research disagrees with the Treg theory at least in part. Interestingly, a recent study demonstrated that post-natal exposure to flame retardents in animals leads to inhibitory functions on the AhR and a reduction of Tregs (Wahl)  and supports that the AhR modulates Treg production (Mezrich) and they may  be a factor at least in some types of reactions to certain toxins.  It would be interesting to examine different Treg ratios and to compare them with patients with MCS that are not GW patients and also compare this to other factors. Specifically, one example would be extenuating circumstances that dramatically effect stress response regulation. From my own experience, I would suggest actual stress and anxiety levels may alter certain markers because my own reactions are significantly different in different environments.

As far as chemical sensitivity, the idea of "loss of tolerance" is relatively new and may involve a better understanding of a "bridge" that links the immune system and metabolic homeostasis.  Because glucose and metabolic dysregulation seems to be concurrent with many environmental illnesses, one must consider metabolic syndrome as a risk factor for any environmental illness and there is little doubt some may contribute to GWS.  Hersoug hypothesizes that diseases like atopy, asthma and autoimmune diseases which are more common with obesity are the result of changes in adipokines including leptin, adiponectin, Il-6 and tumor necrosis factor (Tnf-a) secreted by white adipose tissue.  He adds that body weight contributes to an increase of these inflammatory mediators which in turn down-regulate regulatory T cells which in turn results in a reduction of the anti-inflammatory Il-10. He proposes that this process forms the basis of the idea of "loss of tolerance" and this author believes the loss of "Tregs" contributes significantly to chemical and environmental pollutant sensitivity. Other factors such as endotoxin and loss by genetics or environmental depression of Nrf2 and aberrant AhR signalling may augment the inflammation and allergic and non-allergic reactions and responses and may explain some of the sensitivity to "oil fires".  This may partially be explained by the fact that crude oil and coal dust contain significant amounts of polyaromatic hydrocarbons (PAH) and are ligands for the AhR. (Neff)  They are present in high amounts in diesel exhaust and disruption of the Nrf2 raises allergic airway inflammatory reactions to oxidative stress at much lower levels of diesel exhaust exposure. This may be true and does not dismis some reactions may be a consequence of diesel hydrocarbon content. (Li) Quinatana concludes the AhR, depending on the ligand, is able to modulate both Tregs and Il-17 which is often upregulated in inflammatory autoimmune diseases. It is easy to gather from all of this, that there is probably no simple answer to resolution of environmental disease except to prevent and limit exposures to the "activating" agents.

Of course, one needs to consider the initial "trigger" and the resulting inflammatory immune response may be different through time and be altered through interaction with other other chronic environmental and behavioral factors such as exercise, diet and other noxious "agents" of exposure in one's environment.  The AhR may provide a clue or two because of its role in activation from dioxins and its aberrant signals could be enough to initiate inflammatory responses that may be important in GWS and chemical sensitivity. I have proposed that some of this is due to the communication channel between the Nrf2 and the AhR. Jensen explains that exposure to PAH AhR ligands suppress B cell production and suppress Il-6 and makes an important comment that any alteration in Il-6 can lead to assorted pathologies including autoimmune disease, vitiligo, lupus and multple sclerosis.  Under normal conditions, elevations in Il-6 increase significantly through time in response to endotoxin but when cells are exposed to dioxin or another AhR ligand, cells presented with much lower levels of Il-6. Jensen concludes, "Any environmental chemical capable of compromising this response has the potential to disrupt the regulation of many important stromal cell functions, including generation of inflammatory responses in general and the elaboration of several cytokines, including IL-6, to regulate blood cell development in particular."  In addition, Jensen's research shows that exposures of different AhR ligands including PAH which are prevalent both in indoor and outdoor environments may be different depending on the tissue and may lead to elevations in other inflammatory cytokines such as Tnf-a. Considering that these influences are common in the environment, they can serve to augment responses in GWS or any environmental disease for that matter. (Jensen) One potential consideration is that if alterations in cytokines contribute to blood abnormalities that contribute to hypoxic conditions,
improvements observed with CPAP may reflect improvements in blood parameters of one sort or another. (Incidentally, after my last chemical injury obvious symptoms could have been explained by blood abnormalities like these. Unfortunately, they were not diagnosed because of improper medical care by a licensed practitioner and brings up concerns about access to properly trained practioners for environmental disease which I have discussed at length in other blogs.)

Foster shows that impaired regulation to hypoxic condition in sleep apnea patients and CPAP increases blood flow to normal levels. Another study demonstrates "hypoxia and dioxin response pathways can compete for limiting cellular factor(s) and cross-talk that occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene." (Chan)  This suggests signal dysfunction may influence a battery of physiological and toxicological responses. Most recently in fish, there is evidence that hypoxia reduces the response of the AhR. (Matson) This brings to light two important concerns in light of the discussion here. One is that there is direct interaction between the AhR and the Nrf2 antioxidant system and two, the AhR is an activator of Tregs regulation. In this context, dysfunction could certainly lead to apneas and chronic inflammation. It also may lead to other impairments in the antioxidant system and possibly to chemical sensitivities with a lower Treg production and a "loss of tolerance". It is also worth pondering the extent of effects of blood cell production in relation to circadian rhythm and influence on the positive effects of CPAP (Burioka).

An alternative example of aberrant levels of Il-6 demonstrates the complexity of environmental disease in relation to inflammatory mediators. Curiously, a recent report shows how different factors may be instrumental and  suggest that stress and the effect of pyridostigmine bromide (PB) may be a plausible cause of GWS. Mauck says that his research shows that while stress normally upregulates muscarinic receptor density, the application of  pyridostigmine bromide or physostigmine reduces them. One of the muscarinic targets is the Nrf2 and may suggest a reduction in these receptors may also reduce or prevent the activation of Nrf2. In addition, GSK-3b inhibition also augments muscarinic signals and Treg expression. Thus, conditions where GSK-3b is upregulated may have a negative influence on both chemical sensitivity in GWS and also other types of chemical sensitivity.  The other part of the puzzle in these conditions may be explained and supported by evidence that shows pesticides may contribute to insulin resistance and diabetes and may negatively influence how the body reacts to infection. This could alter inflammatory mediator production and in turn, contribute to the neuroinflammatory process as shown through reductions of Il-6 by GSk-3b inhibition.(Beurel) Dioxins on the other hand, seem to contribute to insulin resistance independant of the AhR. (Hsu)

I have often said in other blogs that environmental illnesses seem more like a failure to adapt and the concept of down-regulation of Tregs provides a viable mechanism for "maladaptation" at least in multiple chemical sensitivity. It may end up that taking genetic expression and immune regulators into account could be what differentiates the forms of chemical sensitivity in autism and MCS from GWS. If Amin is correct and the presence of apneas can be a predictor of  GW syndrome, then one can presume dysregulation of glucose metabolism similar to that that would occur with obesity and the development of chronic inflammation even though GW patients may not be overweight may contribute to GWS. Obesity is a problem in all age groups and classes and is associated with Western diets and GSK-3b may also play its part. It is worth considering that Gulf War veterans that are overweight and eat a typical Western diet will be more at risk for more severe GWI symptoms and those with conditions that depress Nrf2 (which are often diet, exposure and epigenetic influences related) will be even more so!  One may suggest that a lifestyle that promotes healthy eating and low-inflammatory menu like a Mediterranean diet may provide some healthy benefits.





Amin, M. M., Belisova, Z., Hossain, S., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). Inspiratory airflow dynamics during sleep in veterans with gulf war illness: a controlled study. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756111
Gold, A. R., Dipalo, F., Gold, M. S., and Broderick, J. (2004). Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep, 27(3):459-466. http://www.citeulike.org/user/HEIRS/article/7756324
Omurtag, G. Z., Tozan, A., Sehirli, A. O. O., and Sener, G. (2008). Melatonin protects against endosulfan-induced oxidative tissue damage in rats. Journal of pineal research, 44(4):432-438.  http://www.citeulike.org/user/HEIRS/article/2674835
Gulati, K., Banerjee, B., Lall, S. B., and Ray, A. (2010). Effects of diesel exhaust, heavy metals , and pesticides on various organ systems: Possible mechanisms and strategies for prevention and treatment. Indian Journal of Experimental Biology, 48:710-721. http://www.citeulike.org/user/HEIRS/article/7753532
Calero, G., Farre, R., Ballester, E., Hernandez, L., Daniel, N., and Montserrat Canal, J. M. (2006). Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome. Respiratory medicine, 100(5):813-817. http://www.citeulike.org/user/HEIRS/article/7756347
Singh, A. K. and Jiang, Y. Lipopolysaccharide (lps) induced activation of the immune system in control rats and rats chronically exposed to a low level of the organothiophosphate insecticide, acephate. Toxicology and Industrial Health, 19(2-6):93-108. http://www.citeulike.org/user/HEIRS/article/7796
Li, R., Ning, Z., Cui, J., Yu, F., Sioutas, C., and Hsiai, T. (2010). Diesel exhaust particles modulate vascular endothelial cell permeability: implication of zo-1 expression. Toxicology letters, 197(3):163-168.  http://www.citeulike.org/user/HEIRS/article/7284279
Nov, O., Kohl, A., Lewis, E. C., Bashan, N., Dvir, I., Ben-Shlomo, S., Fishman, S., Wueest, S., Konrad, D., and Rudich, A. (2010). Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology, 151(9):4247-4256. http://www.citeulike.org/user/HEIRS/article/7752881
Budhiraja, R. and Quan, S. F. (2009). When is cpap an antihypertensive in sleep apnea patients? Journal of clinical sleep medicine : JCSM, 5(2):108-109. http://www.citeulike.org/user/HEIRS/article/7752952
Amin, M. M., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). The effect of nasal continuous positive airway pressure on the symptoms of gulf war illness. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756404
Hersoug, L.-G. G., Husemoen, L. L., Sigsgaard, T., Madsen, F., and Linneberg, A. (2010). Indoor exposure to environmental cigarette smoke, but not other inhaled particulates associates with respiratory symptoms and diminished lung function in adults. Respirology (Carlton, Vic.), 15(6):993-1000.  http://www.citeulike.org/user/HEIRS/article/7582695
Hersoug, L.-G. G. and Linneberg, A. (2007). The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy, 62(10):1205-1213. http://www.citeulike.org/user/HEIRS/article/1640991
Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., Dorfman, R., Wang, Y., Zielenski, J., Mastronardi, F., Maezawa, Y., Drucker, D. J., Engleman, E., Winer, D., and Dosch, H.-M. M. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature medicine, 15(8):921-929. http://www.citeulike.org/user/HEIRS/article/5398151
El Solh, A. A., Akinnusi, M. E., Baddoura, F. H., and Mankowski, C. R. (2007). Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. American journal of respiratory and critical care medicine, 175(11):1186-1191.  http://www.citeulike.org/user/HEIRS/article/7756664
Burioka, N., Miyata, M., Fukuoka, Y., Endo, M., and Shimizu, E. (2008). Day-night variations of serum interleukin-6 in patients with severe obstructive sleep apnea syndrome before and after continuous positive airway pressure (cpap). Chronobiology international, 25(5):827-834. http://www.citeulike.org/user/HEIRS/article/7748469
Steiropoulos, P., Kotsianidis, I., Nena, E., Tsara, V., Gounari, E., Hatzizisi, O., Kyriazis, G., Christaki, P., Froudarakis, M., and Bouros, D. (2009). Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. Sleep, 32(4):537-543. http://www.citeulike.org/user/HEIRS/article/7756944
Lam, J. C. M. and Ip, M. S. M. Obstructive sleep apnea and the metabolic syndrome: Osa and insulin resistance. Medscape Today. http://www.citeulike.org/user/HEIRS/article/7765845
Gaurdiola, J., Matheson, P., Cavijo, L., Wilson, M., and Fletcher, E. (2001). Hypercoagulability in patients with obstructive sleep apnea. Sleep Medicine, 2(6):517-523. http://www.citeulike.org/user/HEIRS/article/7790684
Nichols, Denise. Original Hypercoagulation Study on Gulf War Veterans. (August 20, 2010) Veterans Today. http://www.veteranstoday.com/2010/08/20/original-hypercoagulation-study-on-gulf-war-veterans/
Salvador, Lourdes. CPAP Machine Improves Gulf War Illness Symptoms for Some. American Chronicle. http://www.americanchronicle.com/articles/view/180225
Espada, S., Rojo, A. I., Salinas, M., and Cuadrado, A. (2009). The muscarinic m1 receptor activates nrf2 through a signaling cascade that involves protein kinase c and inhibition of gsk-3beta: connecting neurotransmission with neuroprotection. Journal of Neural Chemistry, 110(3):1107-1119. http://www.citeulike.org/user/HEIRS/article/7791380
Mauck, B., Lucot, J. B., Paton, S., and Grubbs, R. D. (2010). Cholinesterase inhibitors and stress: Effects on brain muscarinic receptor density in mice. Neurotoxicology. http://www.citeulike.org/user/HEIRS/article/7395495
Beurel, E. and Jope, R. S. (2010). Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience. http://www.citeulike.org/user/HEIRS/article/7264009
Jensen, B., Leeman, R., Schlezinger, J., and Sherr, D. (2003). Aryl hydrocarbon receptor (ahr) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study. Environmental Health: A Global Access Science Source, 2(1):16+. http://www.citeulike.org/user/HEIRS/article/3802484?show_msg=already_posted
Chan, W. K., Yao, G., Gu, Y.-Z., and Bradfiel, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. The Journal of Biological Chemistry, 274(17). http://www.citeulike.org/user/HEIRS/article/7795717
Foster, G. E., Hanly, P. J., Ostrowski, M., and Poulin, M. J. (2007). Effects of cpap on cerebral vascular response to hypoxia in obstructive sleep apnea patients. Respiratory and Critical Care Medicine, 175(7):720-725. http://www.citeulike.org/user/HEIRS/article/7795723
Matson, C. W., Timme-Laragy, A. R., and Di Giulio, R. T. (2008). Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish. Chemosphere, 74(1):149-154. http://www.citeulike.org/user/HEIRS/article/7795748
Neff, Jerry. Bioaccumulation in marine organisms: effect of contaminants from oil well produced water. 2004. Pg 241. http://books.google.com/books?id=ABIQ_FGKOZcC&lpg=PA241&ots=v-kRmNZQY5&dq=polyaromatic%20hydrocarbons%2Bhypoxia&pg=PA241#v=onepage&q&f=false
Li, Y. J. J., Takizawa, H., Azuma, A., Kohyama, T., Yamauchi, Y., Takahashi, S., Yamamoto, M., Kawada, T., Kudoh, S., and Sugawara, I. (2010). Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Clinical immunology (Orlando, Fla.). http://www.citeulike.org/user/HEIRS/article/7730119?show_msg=already_posted
Hsu, H.-F. F., Tsou, T.-C. C., Chao, H.-R. R., Kuo, Y.-T. T., Tsai, F.-Y. Y., and Yeh, S.-C. C. (2010). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3t3-l1 cells. Journal of hazardous materials, 182(1-3):649-655. http://www.citeulike.org/user/HEIRS/article/7383158?show_msg=already_posted
Wahl, M., Guenther, R., Yang, L., Bergman, A., Straehle, U., Strack, S., and Weiss, C. (2010). Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression. Toxicology letters, 198(2):119-126. http://www.citeulike.org/user/HEIRS/article/7408849
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., and Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. Journal of immunology (Baltimore, Md. : 1950), 185(6):3190-3198. http://www.citeulike.org/user/HEIRS/article/7795863
Ho, P. P. and Steinman, L. (2008). The aryl hydrocarbon receptor: a regulator of th17 and treg cell development in disease. Cell Research, 18(6):605-608. http://www.citeulike.org/user/HEIRS/article/3709745

PFOS Significantly Elevates Inflammatory Cytokines From LPS Stimulation.

CiteULike: Subchronic effects of perfluorooctanesulfonate exposure on inflammation in adult male C57BL/6 mice.: "Dong, G.-H. H., Zhang, Y.-H. H., Zheng, L., Liang, Z.-F. F., Jin, Y.-H. H., and He, Q.-C. C. (2010). Subchronic effects of perfluorooctanesulfonate exposure on inflammation in adult male c57bl/6 mice. Environmental toxicology."

Neuroprotective and Anti-inflammatory Activities of Ketogenic Diet on MPTP-induced Neurotoxicity.

Comments: I believe the results of this study are indicative of the fact that a keen understanding of the patients environmental illness and the factors that lead to it are crucial for the best holistic treatment and management of it. It is obvious that a one size fits treatment plan is probably not in the best interest of most patients.

"The change of dopamine was very similar to dopaminergic neurons in the SN. KD inhibited the activation of microglia induced by MPTP in the SN. The levels of proinflammatory cytokines (interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha) in the SN were also decreased and induced by MPTP. So, we concluded that KD was neuroprotective and anti-inflammatory against MPTP-neurotoxicity."

Read more: CiteULike: Neuroprotective and Anti-inflammatory Activities of Ketogenic Diet on MPTP-induced Neurotoxicity.:

Endotoxin-induced Enzyme Causes Depressive Symtoms Before Cytokine/NO Production~!

"IDO by direct application of LPS was preceded by synthesis and secretion of TNFalpha and IL-6 protein and activation of iNOS while IFNgamma expression was undetectable."

CiteULike: Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures

Dioxin Causes Changes in Blood Vessels Through AhR in Developing Zebrafish!

Dioxins: bioaccumulatives chemical compounds formed through combustion and manufacturing. Incidents include backyard burning, applications of herbicides, wastewater treatment, coal-fires, diesel trucks, cigarette smoke, etc(Wipedia)




A recent study shows "activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish." Past studies have demonstrated a significant impact of AhR signaling on the immune system that may also alter the Nrf2 antioxidant system. For this reason, we have suggested an important relationship of AhR and Nrf2 signaling in environmental illness and alterations of blood flow may be a factor in environmental illness symptoms. Dinatale showed AhR signaling initiates an inflammatory cascade that includes Il-6 via Il-1 and NF-kappaB and present in autoimmune and chronic proliferative diseases.




CiteULike: Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish.:



Teraoka, H., Ogawa, A., Kubota, A., Stegeman, J. J., Peterson, R. E., and Hiraga, T. (2010). Malformation of certain brain blood vessels caused by tcdd activation of ahr2/arnt1 signaling in developing zebrafish. Aquatic toxicology (Amsterdam, Netherlands).
http://www.citeulike.org/user/HEIRS/article/7149860

Dinatale, B. C., Schroeder, J. C., Francey, L. J., Kusnadi, A., and Perdew, G. H. (2010). Mechanistic insights into the events that lead to synergistic induction of il6 transcription upon activation of the ah receptor and inflammatory signaling. The Journal of biological chemistry.
http://www.citeulike.org/user/HEIRS/article/7339715

Hormone Modulates Immune Cell Activation after Cigarette Smoke Exposure in Mice.

Recent study says leptin may modulate the immune responses from cigarette smoke. Other studies demonstrate that leptin and Il-6 may be involved with sickness syndrome and may include modulation of hormones that regulate behavior such as orexins and may contribute to inflammation-induced insulin resistance.

Notes: Recent study also demonstrates that cigarette smoke induced epigenetic changes in epithelial cells in vitro that may contribute to cancer growth.

CiteULike: Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice.: "Vernooy, J. H., Bracke, K. R., Drummen, N. E., Pauwels, N. S., Zabeau, L., van Suylen, R. J. J., Tavernier, J., Joos, G. F., Wouters, E. F., and Brusselle, G. G. (2010). Leptin modulates innate and adaptive immune cell recruitment after cigarette smoke exposure in mice. Journal of immunology (Baltimore, Md. : 1950)."


HEIRS H&H






Harden, L. M., du Plessis, I., Poole, S., and Laburn, H. P. (2006). Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior. Physiology & behavior, 89(2):146-155.
http://www.citeulike.org/user/HEIRS/article/4745011
Liu, F., Killian, J. K., Yang, M., Walker, R. L., Hong, J. A., Zhang, M., Davis, S., Zhang, Y., Hussain, M., Xi, S., Rao, M., Meltzer, P. A., and Schrump, D. S. (2010). Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene, aop(current).
http://www.citeulike.org/user/HEIRS/article/7154109

Il-6 Modulates CRF in the Hypothalamus in Response to Different Signals.

Module: 5/22/2010

Background: CRF can regulate signaling in response to different odors. In those cases, it can lead to an anxiolytic or elevation and other responses typical of the stress response including pain generation, immune regulation, itch, rash and other changes such as gastric function alterations. Of course, these are symptoms characteristic of chemical sensitivity and also some symptoms characteristic of other environmentally influenced conditions such as CFS and sickness syndrome.

A major regulator of sickness syndrome is Il-6 which can be functionally modulated through Il-10 and ultimately most probably HO-1 which has been shown in other studies to increase during exercise. Interestingly, one can identify similarities in cancer-related fatigue to some chronic symptoms of CFS and sickness syndrome including the exhausting fatigue and cachexia that is exhibited in the latter, in animals and humans. Preliminary studies suggest cytokine Il-6/Il-8 may modulate the severity of cancer-related fatigue and others show cancer-related fatigue is common with serotonin dysregulation. Coincidentally, in the trout corticotrophin activation by ammonia is associated with alterations in neurotransmitter levels including dopamine and serotonin. So here again, we see potential especially with periods of aberrant corticotrophin signalling, where symptoms of environmental illness such as anxiety, depression, weakeness and fatigue may present itself. These findings supports past studies that suggest that fatigue in CFS may be in part due to serotonin dysregulation and elevations in Il-6.(Ryan)

CiteULike: Transcriptional regulation of hypothalamic corticotropin-releasing factor gene.: "Glucocorticoid-dependent repression of cAMP-stimulated CRF promoter activity is mediated by both nGRE and SRE in hypothalamic cells. Interleukin (IL)-6 produced in the hypothalamus stimulates the CRF gene. Suppressor of cytokine signaling-3, which is induced by a cAMP stimulant and IL-6, is involved in the negative regulation of CRF gene expression in hypothalamic cells. Such complex mechanisms would contribute to stress responses and homeostasis in the hypothalamus."

Related: Hummel, M., Cummons, T., Lu, P., Mark, L., Harrison, J. E., Kennedy, J. D., and Whiteside, G. T. (2010). Pain is a salient ßtressor" that is mediated by corticotropin- releasing factor-1 receptors. Neuropharmacology.
http://www.citeulike.org/user/HEIRS/article/7177466
Coric, V., Feldman, H. H., Oren, D. A., Shekhar, A., Pultz, J., Dockens, R. C., Wu, X., Gentile, K. A., Huang, S.-P. P., Emison, E., Delmonte, T., D'Souza, B. B., Zimbroff, D. L., Grebb, J. A., Goddard, A. W., and Stock, E. G. (2010). Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depression and anxiety, 27(5):417-425.
http://www.citeulike.org/user/HEIRS/article/7193107
Theoharides, T. C., Singh, Boucher, W., Pang, X., Letourneau, R., Webster, E., and Chrousos, G. (1998). Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology, 139(1):403-413.
http://www.citeulike.org/user/HEIRS/article/7207688
Mustian, K. M., Fisher, S., Adams, J., Janelsins, M., Palesh, O., Darling, T., Peppone, L., Heckler, C., Williams, J., and Morrow, G. (2009). Cytokine-mediated changes associated with improvements in cancer-related fatigue induced by exercise: Results from a randomized pilot study of cancer patients receiving radiotherapy. Journal of Clinical Oncology, 27(15s).
http://www.citeulike.org/user/HEIRS/article/7207720
Ryan, J. L., Carroll, J. K., Ryan, E. P., Mustian, K. M., Fiscell, K., and Morrow, G. R. (2007). Mechanisms of cancer-related fatigue. The Oncologist, 12(1 supp):22-34.
http://www.citeulike.org/user/HEIRS/article/7207823

How odors activate the stress response and inflammatory mediators!

"enhanced IL-6 activity may stimulate the HPA axis at the level of the hypothalamus via a CRH-mediated mechanism For example, inhalation of citralva, a sample used during the study, may enhance the stress response or may itself act as a stress."


Effects of Odorants on the Hypothalamic-Pituitary-Adrenal Axis and Interleukin-6 (IL-6) and IL-6 Receptor mRNA Expression in Rat Hypothalamus after Restraint Stress -- Komori et al. 28 (9): 767 -- Chemical Senses: "enhanced IL-6 activity may stimulate the HPA axis at the level of the hypothalamus (Naitoh et al., 1988; Fukata et al., 1989; Navarra et al., 1991; Tominaga et al., 1991) via a CRH-mediated mechanism (Navarra et al., 1991; Lyson and McCann, 1992), i.e. inhalation of citralva may enhance the stress response or may itself act as a stress."

Gram (+) Bacterial Component Strongly Enhances Inflammatory Response in Rheum Arthritis...

CiteULike: Lipoteichoic acid enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, PKCdelta and c-Src dependent pathways.: "Tang, C.-H. H., Hsu, C.-J. J., Yang, W.-H. H., and Fong, Y.-C. C. (2010). Lipoteichoic acid enhances il-6 production in human synovial fibroblasts via tlr2 receptor, pkcdelta and c-src dependent pathways. Biochemical pharmacology, 79(11):1648-1657."

Dysregulated immune balance in lupus.

Our data indicate that the mechanisms involved in balancing Th1 and Th17 regulation, as well as in producing IL-6, are aberrant in SLE, leading to an increased Th17 response.

CiteULike: Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus: "Shah, K., Lee, W. W., Lee, S. H., Kim, S. H., Kang, S. W., Craft, J., and Kang, I. (2010). Dysregulated balance of th17 and th1 cells in systemic lupus erythematosus. Arthritis Research & Therapy, 12(2):R53+."

Individual Responses to Volatile Contaminants Are Influenced By Genetic Makeup

Definition:
Aerosol:suspension of fine solid particles or liquid droplets in a gas. Examples are smoke, oceanic haze, air pollution, smog and CS gas. The word aerosol derives from the fact that matter "floating" in air is a suspension. (Wipedia)
Particulate Matter: are tiny subdivisions of solid or liquid matter suspended in a gas or liquid.
Redox potential (reduction potential): a tendency of a chemical species to acquire electrons and thereby be reduced.
Electrophile: electron lover- a substance that accepts an electron pair. Carbonyls and acids are examples.
quinone: a class of organic compounds that are formally derived from aromatic compounds.


Background: In other blogs, we have explained how particulate matter is a health hazard and the smaller or more fine the particulate the more likely it is to cause a heightened inflammatory response. There are several reasons for this but two important ones are because they have a larger surface area to bind with other contaminants and they are small enough to reach the deeper part of the lungs (if inhaled) or digestive tissue (if ingested) and infiltrate lower levels of tissue where they increase inflammation. Recently, a study of mice demonstrated how different strains have different basal levels of antioxidant genes that could potentially cause a increased or decreased risk for health consequences. In this case, it was a model for COPD which is an inflammatory respiratory disease and cigarette smoke. One can conclude from the results of this study and if the same is true for humans as it is for mice, different ethnic groups, lineages, etc. may be more susceptible than others to environmental contaminants. Interestingly, different mouse strains exhibit differences in basal levels of proinflammatory cytokines, oxidative stress and also expression of antioxidant genes Nrf2, HO-1, glutathione and others including IL-6. (Vecchio) These results augment controversial findings that suggest infections are less environmental than they are genetic and a person's susceptibility and ability to recover has to do less with environmental factors than it does genetics. (EurekAlert)

A few new studies shed a little bit more light on the chemical properties of PM and provides support for the idea that "semi-volatile and volatile contaminants have been implicated in causing adverse health effects. From this study, the author examined hazard levels in regards to the particle or vapor in an aerosol. He explains that redox-active components are particle-phase and vapors are more electrophilic and noted that latter contaminants were capable of inducing HO-1, a strong antioxidant and stress response protein. From this he concluded that volatile properties should be considered when determining the hazardous nature of a contaminant." While this may seem like greek to some, a general conclusion one can make from this is volatile properties of contaminants have adverse health effects. In addition, an investigator must be cognizant and consider genetic expression may influence a person's immune response to environmental contaminants including those that are volatile vapors.

Comment: The findings of these studies should have important influence on treatments descisions for MCS patients.


Vecchio, D., Arezzini, B., Pecorelli, A., Valacchi, G., Martorana, P. A. A., and Gardi, C. (2010). Reactivity of mouse alveolar macrophages to cigarette smoke is strain dependent. American journal of physiology. Lung cellular and molecular physiology. http://www.citeulike.org/user/HEIRS/article/6675046?show_msg=already_posted
Eiguren-Fernandez, A., Shinyashiki, M., Schmitz, D. A., Distefano, E., Hinds, W., Kumagai, Y., Cho, A. K., and Froines, J. R. (2010). Redox and electrophilic properties of vapor- and particle-phase components of ambient aerosols. Environmental research. http://www.citeulike.org/group/7769/article/6704033
(2010). Rockefeller scientist to speak at aaas on infections as genetic disorders.
http://www.citeulike.org/user/HEIRS/article/6704247
Shinyashiki, M., Eiguren-Fernandez, A., Schmitz, D. A., Di Stefano, E., Li, N., Linak, W. P., Cho, S.-H. H., Froines, J. R., and Cho, A. K. (2009). Electrophilic and redox properties of diesel exhaust particles. Environmental research, 109(3):239-244. http://www.citeulike.org/group/7833/article/6705178

Immune Differences Between Mice Strains Determine Susceptibility to Cigarettte Smoke

Snippet: Strain A and B showed differences in baseline production of ROS and H2O2 and also glutathione, Nrf2, heme oxygenase 1 and GPX2. This was associated with reduced HDAC2 expression, activation of NF-kappaB and higher basal levels of TNF-alpha and IL-6. CSE induced a decrease in HDAC2 protein levels strains, however, the level of HDAC2 was significantly lower in strain A than in strain B. (Names of mouse strains have been changed for purpose of simplicity.)
Comment: One can assume from this there is significant potential for different people (because of their genetic makeup that results in different expression of antioxidant and immune genes) to be more prone to the health consequences of cigarette smoke. This has important implication for health conditions including but not limited to conditions like COPD, asthma and also other conditions like MCS.

For further reading: Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease

Blog Tags: Nrf2 , HO-1 , Tnf-a, Il-6



CiteULike: Reactivity of Mouse Alveolar Macrophages to Cigarette Smoke is Strain Dependent.: "Vecchio, D., Arezzini, B., Pecorelli, A., Valacchi, G., Martorana, P. A. A., and Gardi, C. (2010). Reactivity of mouse alveolar macrophages to cigarette smoke is strain dependent. American journal of physiology. Lung cellular and molecular physiology."

Fat tissue as an endocrine organ.

Immune cells "macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes.

Adipose tissue as an endocrine organ.: "Galic, S., Oakhill, J. S., and Steinberg, G. R. (2010). Adipose tissue as an endocrine organ. Molecular and cellular endocrinology, 316(2):129-139."

Neuroinflammation,Diabetes and GSK-3b in Environmental Illnesses

Background: In other blogs, we have described how different proteins interact in molecular pathways to achieve specific metabolic processes. Most often we focus on the Nrf2-PGC-1a-SIRT1 pathway because activation or non-activation will effect cell survival. Recently, we spent quite a bit of time discussing the importance of PGC-1a for metabolic homeostasis and energy metabolism. Friedrich's ataxia is a neurodegenerative conditions that strikes early in life and have used FA as an example for comparison of complications of diseases that arise from Nrf2 dysfunction. Newer studies show that some of the complications in FA arise from dysregulation of PPAR-gamma and PGC-1a and symptoms associated with this dysfunction includes insulin resistance, cardiomyopathy and diabetes. Generally, dysregulation of the PPAR-gamma pathway which is anti-inflammatory leads to abherrant signaling from NF-kappaB. NF-kappaB increases mediation of inflammatory cytokines and in addition to inflammation and other health-related consequences, overexpression of NF-kappaB may alter drug metabolism including CYP3A4 which is responsible for the detoxification of over 50% of the drugs currently marketed.


Some of the most severe complications of environmental illnesses occur from neuroinflammation from inflammatory signals initiated through TLR and NF-kappaB. Under normal conditions, a number of different proteins interact to provide protective mechanisms to prevent inhibition of cellular function. It has been shown that GSK-3b overactivation is a major contributor to neuroinflammation through its role in the disruption of the blood brain barrier (Ramirez) and is at least in part, responsible for complications of a number of neurodegenerative diseases including PD. The activation of GSK-3 increases the production of a number of cytokines including IL-6 and inhibits IL-10. Both PPAR-gamma and another anti-inflammatory Il-10 that modulates sickness syndrome cytokines can inhibit GSK-3b. The over expression of the latter using a kind of "feedback mechanism". In addition to preventing neuroinflammation, GSK-3b inhibition also stabilizes PGC-1a and important regulator of normal mitochondrial biogenesis and energy metabolism. Other studies have showed that GSK-3b also inhibits glycogen synthase that regulates long term energy storage and may account for some of the weight problems reported in those with EI. This hormone is also inhibited by epinephrine and therefore, one may suggest that stress and overactive expression of GSK-3b may potentiate the effects of each other and further exacerbate complications of energy metabolism. In addition, this protein has been implicated as a factor contributing to a number of what are suspected to be neural inflammation-induced mental health conditions including autism, bipolar disorder, other mood disorders, Alzheimer's disease and others.  Incidentally, studies have demonstrated that both endotoxin may influence the activation of GSK-3b. Endotoxin has been implicated as a factor in environmental illness including chronic fatigue syndrome and it has been shown that endotoxin infection-induced GSK-3b by Tnf-a leads to a "synergistic effect" of increasing nitric oxide and reduction of IL-10 while promoting IL-6. GSK-3b, although a necessary protein, has potential for being a therapeutic target for a number of health conditions, including several that are under the "umbrella" of environmental illness. Several months ago we blogged about the evolutionary development of IGF-1 and its relationship to the olfactory system as well as DAF-16 and SKN-1 in lower organisms. Heavy metals may inhibit IGF-1 during the methionine cycle and is a common constituent of air pollution and particulate matter. Bondy explains how IGF-1 has an inhibitory effect on GSK-3b and has direct effects on neural growth and survival during brain development. She further explains how GSK-3b contributes to the loss of olfactory and dentate neurons when IGF-1 is underexpressed which may be important considering that environmental illnesses often present with loss of olfactory function and /or dysregulation.(Bondy) On the other hand , reductions in IGF-1 expression promote longer lifespans and reduce effects of endotoxemia while abherrant IGF-1 signaling may contribute to neuropathic pain, especially in diabetes. (Pabbidi) During nerve injury {ie lead (Williams), low-level toluene(Fujimata)}, NGF (Nicols) can activate both GSK-3b and nociceptors generating inflammatory pain.(Gould) Nociceptive behaviors have been implicated in MCS. (Pall)

Notes:

• EGCG, a compound in green tea, can suppress neurotoxicity by inhibiting GSK-3b.
• Exercise may positive influence the expression of glycogen synthase by inhibiting GSK-3b in skeletal muscle.
• Aging influences increased expression of GSK-3b. (Mercado-Gomez)

For Further Reading:

• GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
• Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness

Original article and citations located here.

Depression, traumatic stress and interleukin-6

Depression, traumatic stress and interleukin-6: "URL: Depression, traumatic stress and interleukin-6

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Read and find out more...

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Depression, traumatic stress and interleukin-6

Bob, P., Raboch, J., Susta, M. M., Pavlat, J., Jasova, D., Vevera, J., Uhrova, J., Benakova, H., and Zima, T. (2010). Depression, traumatic stress and interleukin-6. Journal of Affective Disorder, 120(1):231-234. http://www.citeulike.org/user/HEIRS/article/6389597

High-intensity interval training attenuates the exercise-induced increase in plasma IL-6 in response to acute exercise

High-intensity interval training attenuates the exercise-induced increase in plasma IL-6 in response to acute exercise: "URL: High-intensity interval training attenuates the exercise-induced increase in plasma IL-6 in response to acute exercise

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