Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation

Seems to me that the findings from this author are pretty important....:)

"up-regulation of HO-1 in astrocytes is associated with down-regulation of iNOS expression and thereby NO production, an effect that involves the p38 MAPK signaling pathway, which suggests that this glial cell response could play an important protective role against oxidative stress in the brain."

"Sheng, W., Hu, S., Nettles, A., Lokensgard, J., Vercellotti, G., and Rock, R. (2010). Hemin inhibits no production by il-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 mapk activation. Journal of Neuroinflammation, 7(1):51+."

Read more: CiteULike: Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation:

New Findings Involving Enxymes that Promote Protective Effects of Hydrogen Sulfide.

Background: It has been suggested that individuals with chemical sensitivity are more susceptible to the effects of hydrogen sulfide even though hydrogen sulfide has beneficial effects at low endogenous or exogenous levels. It has been shown that some of the benefits of H2S are regulated through Nrf2 and HO-1. In Nrf2 knock-outs, H2S fails to elicit the strong antioxidant HO-1 and reduces tissue resistance to oxidative stress.

H2S protects tissue and " is an endogenously produced gaseous signaling molecule with a diverse physiological profile. Its production in mammalian systems has been attributed to 2 key enzymes in the cysteine biosynthesis pathway, cystathionine β-synthase (CBS) and cystathionine -lyase (CGL). A new study provides evidence that animals lacking either CBS or CGL may be more suceptible to oxidative stress but have slightly different presentations diagnostically. The latter may require supplementation with cysteine in deficiency.  In either case, the inability to synthesize or utilize H2S may contribute to environmental illnesses.


Calvert, J. W., Jha, S., Gundewar, S., Elrod, J. W., Ramachandran, A., Pattillo, C. B., Kevil, C. G., and Lefer, D. J. (2009). Hydrogen sulfide mediates cardioprotection through nrf2 signaling. Circ Res, 105(4):365-374. http://www.citeulike.org/user/HEIRS/article/5211207?show_msg=already_posted
Ishii, I., Akahoshi, N., Yamada, H., Nakano, S., Izumi, T., and Suematsu, M. (2010). Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury. Journal of Biological Chemistry, 285(34):26358-26368. http://www.citeulike.org/user/HEIRS/article/7657999

Endotoxin and Loss of Tolerance via Reduced HO-1: Potential Mechanism in CFS and MCS?

It has been suggested that chemical sensitivity and possibly other environmental illness conditions can be the result of a "loss of tolerance".  Notably, this "loss of tolerance" may be the result of altered signaling of the immune response and contrbuting factors may include the presence of endotoxin which can 1) activate inflammatory responses, 2) reduce the threshold of reactions to allergens and 3) alter gene expression from ROS and alterations in methylation. In addition, endotoxin through activtion of GSK3b provides a mechanism to "deactivate" the antioxidant system, Nrf2. High fat diets and hyperglycemia may also promote the translocation of bacteria in the respiratory and intestinal tract. This may further increase inflammation and promote neuroinflammation in the brain as a consequence of cytokine activity in the intestinal tract and liver. At some point, the break down of the blood brain barrier may increase the likelihood of brain inflammation and changes in behavior and neurotransmission.

A recent study provides support for the hypothesis of "loss of tolerance" in environmental illness because of the role of Nrf2 as a master regulator of detoxification.  Heme oxygease is an antioxidant that is regulated by Nrf2. Naidu explains that past research has demonstrated that HO-1 deficient animals are highly susceptable to toxicity from endotoxin. Further " the potential significance of HO-1 in the adaptive immune system has been implied by a recent report, in which genetic deficiency of HO-1 decreased the suppressive activity of regulatory T cells (8)." This loss of supression could suggest a possible explanation of some symptoms related to environmental illness, especially chemical sensitivity and to some extent chronic fatigue syndrome.  There is debate on the benefits and potential harmful effects of  exercise on the latter and there are now a number of reports that demonstrate that exercise elevates HO-1 expression. On the other hand, it also can lead to an increase of translocation of bacteria that are alway present in the gut, even though the balance of gut may be different at one point vs another. In any event, the effect of exercise on bacteria translocation and HO-1 levels offer an explanation why some patients improve with exercise while others do not. As Naidu explains, there may be multiple pathways for the expession of HO-1 and may be species specific. Interestingly, he does point out that inhibition of the P38 pathway contributes to HO-1 expression at least in this study and this expression occurs via regulation by Nrf2 and reactive species are involved with this activation. This supports other research that blockade of the P38 pathway increases the expression of NO by endotoxin.


Naidu, S., Vijayan, V., Santoso, S., Kietzmann, T., and Immenschuh, S. (2009). Inhibition and genetic deficiency of p38 mapk up-rregulates heme oxygenase-1 gene expression via nrf2. Journal of Immunology, 182:7048-7057.  http://www.citeulike.org/user/HEIRS/article/7586285

DHA Suppresses Neuroinflammatory Responses and Induces Heme Oxygenase-1 Expression in BV-2 Microglia: Implications of Antidepressant Effects for Omega-3 Fatty Acids.

CiteULike: Docosahexaenoic Acid Suppresses Neuroinflammatory Responses and Induces Heme Oxygenase-1 Expression in BV-2 Microglia: Implications of Antidepressant Effects for Omega-3 Fatty Acids.: "Lu, D.-Y. Y., Tsao, Y.-Y. Y., Leung, Y.-M. M., and Su, K.-P. P. (2010). Docosahexaenoic acid suppresses neuroinflammatory responses and induces heme oxygenase-1 expression in bv-2 microglia: Implications of antidepressant effects for omega-3 fatty acids. Neuropsychopharmacology."

Different Susceptibility to Parkinson's in Mice Lacking Nrf2 vs. HO-1~!

"HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols"

Read abstract: Different Susceptibility to the Parkinson's Toxin ... [PLoS One. 2010] - PubMed result:

The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation -- Innamorato et al. 181 (1): 680 -- The Journal of Immunology

The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation -- Innamorato et al. 181 (1): 680 -- The Journal of Immunology: "Model proposed for modulation of microglia by the Nrf2/HO-1 axis. Pathogenic or neurotoxic insults (LPS) interact with pattern recognition receptors (TLR4) and trigger the early release of NADPH oxidase-mediated ROS and other proinflammatory factors. The increase of intracellular ROS is then detected by Nrf2, guardian of redox homeostasis, which activates a set of antioxidant and anti-xenobiotic genes, including HO-1. This late antioxidant response restores the redox balance, inhibits NADPH oxidase and down-regulates TLR4, driving active microglia back to the resting state. Genetic variability in key antioxidant enzymes, environmental alterations, or just the normal decline of redox homeostasis that occurs with aging leads to inefficient redox control and reduced capacity to down-modulate active microglia. This fact results in microglial activation and brain damage. Pharmacologic action on the Nrf2/HO-1 axis reinforces or restores microglial redox control, strengthens the negative loop, and assists in reduction of neuroinflammation."

NO/cGMP signaling pathway limits inflammatory degeneration of dopaminergic neurons: via regulation of HO-1

"NO-cyclic GMP signaling pathway promotes the induction of HO-1 specifically in dopaminergic neurons, which acts as an endogenous protective system to limit inflammatory degeneration of this cell population."

CiteULike: Nitric oxide-cyclic GMP signaling pathway limits inflammatory degeneration of midbrain dopaminergic neurons: cell type-specific regulation of heme oxygenase-1 expression.:

HO-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor.

CiteULike: Heme oxygenase-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor.: "cytoprotective functions of HO-1 in LPS-induced lung injury are associated with negative regulation of lung MIF and TLR4-induced inflammatory response."

Fibroblast growth factor 9 upregulates heme oxygenase-1 and gamma-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity.

"Fibroblast growth factor upregulates gamma-GCS and HO-1 expression to protect cortical and dopaminergic neurons from MPP(+)-induced oxidative insult."

CiteULike: Fibroblast growth factor 9 upregulates heme oxygenase-1 and gamma-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity.:

Resveratrol Metabolites Induces HO-1 via Nrf2 through KEAP1 Residue Modification.

It is hence likely that piceatannol modifies specific cysteine residues of Keap1, which allows Nrf2 to translocate into the nucleus and bind to ARE, leading to enhancement of the expression of HO-1. The characteristic catechol moiety of piceatannol appears to be critical for induction of Nrf2 activation and subsequent upregulation of HO-1.

CiteULike: Piceatannol induces heme oxygenase-1 expression in human mammary epithelial cells through activation of ARE-driven Nrf2 signaling.: "Lee, H.-H. H., Park, S.-A. A., Almazari, I., Kim, E.-H. H., Na, H.-K. K., and Surh, Y.-J. J. (2010). Piceatannol induces heme oxygenase-1 expression in human mammary epithelial cells through activation of are-driven nrf2 signaling. Archives of biochemistry and biophysics."

Glutamine Synthetase, PFOS and Neurotransmission

PFC are chemicals that are ubiquitous in the environmental and can or could be found in products including building materials, fabrics, packaging, clothing, protective gear etc. Recent studies show that these chemicals have the capacity to regulate or impair gene expression including those that regulate the excretion of toxic waste products that may result in alterations of neurotransmission and contribute to their toxicity. In addition, genetic problems may aggravate this inhibition and augment the physical consequences of exposure. Glutamine synthetase is one enzyme that is important for regulation of toxins such as ammonia in the brain as well as production of glutathione. In addition, certain conditions, such as in endotoxemia and implicated as a causal factor is CFS, the activity of this enzyme is further reduced. Nrf2 is protective against PFOS through the generation of HO-1 and reductions in its production may augment oxidative stress damage from PFOS.


Yang, X., Wang, L., Sun, W., and Xue, Z. (2009). [effects of perfluorooctane sulfonate on amino acid neurotransmitters and glutamine synthetase in rats]. Wei sheng yan jiu = Journal of hygiene research, 38(1):19-21. http://www.citeulike.org/user/HEIRS/article/6999108
Häussinger, D. and Schliess, F. (2007). Glutamine metabolism and signaling in the liver. Frontiers in Bioscience, 12:371-391.
http://www.citeulike.org/user/HEIRS/article/7208003
Shi, X. and Zhou, B. (2010). The role of nrf2 and mapk pathways in pfos-induced oxidative stress in zebrafish embryos. Toxicol. Sci., 115(2):391-400.
http://www.citeulike.org/user/HEIRS/article/6761678

Up-regulation of expression of HO-1 through CaMKII-ERK1/2-Nrf2 signaling mediates the anti-inflammatory effect of bis-demethoxycurcumin in LPS-stimulated macrophages.

Up-regulation of heme oxygenase-1 expression through CaMKII-ERK1/2-Nrf2 signaling mediates the anti-inflammatory effect of bis-demethoxycurcumin in LPS-stimulated macrophages.

Toluene regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma.

Concept: Toluene is a chemical that needs to be handled correctly to prevent occupational injury.

New study suggests therapeutic approaches to elevate HO-1/Ferritin through the Nrf2 pathway may help alleviate symptoms from exposure to toluene.

Read more about: HO-1 tag in the library and on the Blog: Tag HO-1.















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CiteULike: Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma.: "Kim, S.-H. H., Choi, G.-S. S., Ye, Y.-M. M., Jou, I., Park, H.-S. S., and Park, S. M. (2010). Toluene diisocyanate (tdi) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma. Clinical and experimental immunology."

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."

Protein Important for Mitochondrial Biogenesis Cooperates With HO-1 To Increase Stress Resistance In Endothelial Cells

ConclusionWe have identified an important relationship between PPARdelta, PGC1alpha, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARdelta ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARdelta represents a potentially important therapeutic target in the vasculature.

CiteULike: PPARdelta and PGC1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress: "Ali, F., Ali, N. S., Bauer, A., Boyle, J. J., Hamdulay, S. S., Haskard, D. O., Randi, A. M., and Mason, J. C. (2010). Ppardelta and pgc1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress. Cardiovasc Res, 85(4):701-710."

Impairments in Muscle Function After Cigarette Exposure and Environmental Illness

PGC-1a a protein factor necessary for mitochondrial function and may be reduced with exposure to LPS as well as, from impairments in Nrf2. This study demonstrates that TNF-a (already identified as a factor in CFS and Parkinson's) is generated from exposure to cigarette smoke (and lots of other environmental contaminants) and has been shown to down-regulate PGC-1a that may lead to vascular and myocyte dysfunction. PGC-1a also regulates a number of glucose transporters such as GLUT1 and GLUT4 which trasport glucose into cells.  When one looks at a condition related to glucose uptake from impairment of glucose transporters such as in GLUT1 deficiency, there are recognizable patterns of impairment one may recognize in other environmental illnesses including CFS and fibromyalgia and also described as Parkinsonism and ataxia-like symptoms.  Because Nrf2 contributes to PGC-1a expression, a deficiency in Nrf2 may also present with these types of symptoms impaired after cigarette exposure and particulate matter from diesel exhaust. Of course, other factors such as accumulation of ammonia and genetic SNP may also pose potential cellular threats. PGC-1a can be increased through exercise but this will be dependant on the availabity of NRF1 (another protein) regulated by Nrf2/HO-1. Sauna and Waon therapy have been shown to elevate PGC-1a and Nrf2. Deficiencies of PGC-1a may exacerbate the autoimmune-type presentation of environmental illness in Nrf2 deficiencies which produce less HO-1. Lack of PGC-1a and Nrf2 may contribute to the development of chronic diabetes in addition to other metabolic complications and numerous other conditions, such as cardiovascular disease.


For review:

• Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!
• Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
• Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer
• T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

CiteULike: TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure.: "Tang, K., Wagner, P. D., and Breen, E. C. (2010). Tnf-alpha-mediated reduction in pgc-1alpha may impair skeletal muscle function after cigarette smoke exposure. Journal of cellular physiology, 222(2):320-327."





Lihua CHE, N. and Chiwai WON, G. Estrogen-related receptor a inverse agonist enhances basal glucose uptake in myotubes through reactive oxygen species. Biological Pharmacology Bulletin, 32(7):1199-1203. http://www.citeulike.org/user/HEIRS/article/6512026
Arany, Z., Foo, S.-Y. Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., Baek, K. H. H., Rosenzweig, A., and Spiegelman, B. M. (2008). Hif-independent regulation of vegf and angiogenesis by the transcriptional coactivator pgc-1alpha. Nature, 451(7181):1008-1012. http://www.citeulike.org/user/HEIRS/article/2406298
Pons, R., Collins, A., Rotstein, M., Engelstad, K., and De Vivo, D. C. (2009). The spectrum of movement disorders in glut-1 deficiency. Movement Disorders, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/6512017
Piantadosi, C. A., Carraway, M. S., Babiker, A., and Suliman, H. B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res, 103(11):1232-1240. http://www.citeulike.org/user/HEIRS/article/4617070?show_msg=already_posted
Glucose Transporter. Wipedia. Retrieved January 10, 2009.

Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!

I recently discussed how IL-10 determines the severity and length of sickness syndrome. At that time, I suggested chemical sensitivity is a loss of tolerance caused by an imbalance of T regulator cells and dysfunction of Nrf2 and based this assumption on a recent study showing environmental pollutants may lead to a decrease in the expression of Tregs whereas, normally chronic exposure increases them. In previous animal studies, the loss of Tregs results in the development of "immediate autoimmune-type disease."

The paragraphs below will provide more support for the idea that Nrf2 does indeed play a role in environmental illness including MCS in particular. First of all, it is important to review that environmental illnesses usually include allergy, asthma, inflammatory bowel disease, diabetes, lyme disease, heavy metal disease, chemical sensitivity, just to name a few. Generally, environmental illnesses may be categorized as Th1 or Th2 according to their T cell pathway subset which is either considered to be cell-mediated or humoral , respectively. Vodjani provides a graphical representation of environmental illnesses in relation to autism in his article and classifies them as Th1 or Th2. He classifies chemical sensitivity as a Th2 humorally- regulated autoimmune disease along with allergy and asthma. Tregs, as he describes, are cells that try to negotiate a balance between cells that suppress and ones that maintain homeostasis. More simply, they are T cells with specific markers. Personally, I have dubbed them to be immune cell referees!

This is how he classifies the autoimmune diseases:

Th1 Autoimmune Disease

• mulptiple sclerosis
• diabetes
• arthritis
• uveitis
• lyme disease
• mercury-induced autoimmunity
• atopic dermatitis (initiation phase)
• inflammatory bowel disease
• bacterial infection
• mold infection

Th2 Autoimmune Disease

• lupus erythematosis
• lead-induced autoimmune disease
• allergy
• asthma
• chemical sensitivity
• parasitic infection
• atopic dermatitis (acute phase)
• inflammatory bowel disease
• bacterial infection
• malignancy

This author also describes the steps involved when conditions in the intestinal tract initiate autoimmune disease and brain disfunction/ neurodegeneration. These steps are as follows:

1. mucosal immune abnormalities
2. imbalanced gut flora
3. intestinal barrier diysfunction
4. systemic inflammation
5. neuroinflammation
6. neuroinvasion
7. neurodegeneration

In support of the idea of chemical sensitivity as an autoimmune disease one needs to understand the concept of loss of tolerance which include loss of Tregs and loss of suppression of inflammatory initiators. This loss may depend on other proteins such as Il-10 and HO-1 which are ultimately directed or indirectly regulated by Nrf2. For instance, it has been demonstrated Nrf2 -/- cells express lower HO-1 which is necessary for Treg suppression.  Tregs levels also are negatively influenced by high-fat (Ma), age, mental stress, are differentially regulated by different AhR ligands (Quintana) and vitamin D levels. The last of which also decreases with age.

Williams and his team provides more insight into how the expression of Nrf2 is different with exposure to environmental pollutants. This article is long and the author makes several points worth discussion that support the notion of the possible involvement of Nrf2 in chemical intolerance. Initially the researcher describes how Nrf2 deficiency may stimulate a Th2 response according to the type of pollutant such as particulate matter. He admits even after presenting his findings, exposures to mixed pollutants are hard to analyze but he believes he uses an approach to match a "real-world" setting. His findings provide a mechanism for how certain environments tend to be more reactive to certain people and why these reactions do not always "appear" to be allergenically-mediated. Through this study, the researcher demonstrates Nrf2 positive and Nrf2 deficient animals show different immune profiles when exposed to different pollutants. For example, he found IL-18 was increased in Nrf2 positive but decreased in Nrf2 deficiency. This suggests Nrf2 regulates Il-18 which plays a role in inhibiting IgE in B cells. Typically, IL-18  is associated with some types of allergy, most often bacterial or viral and curiously, it is elevated in chronic autoimmune urticaria (itchy rash). (Ibrahim) Also, Nrf2-/- show lower protein CD40 that regulate IgE response which may include mild allergy-type responses like in hay fever to life threatening symptoms of anaphylactic shock. Nrf2 levels can fluctuate and if alterations of CD40 and IgE reflect this, it may explain why IgE profiles are often "scewed" in MCS patients. Williams also demonstrated that NAC, a common antioxidant used in MCS therapy has both positive and negative immune effects depending on the type of exposure to the point it may influence the Th1 or Th2 subtypes and may explain why some patients have good luck with NAC therapy and others do not.  It also makes it evident that MCS treatments need to be medically-focused and individualized, why control of environmental stressors are critical and at least for the present, no "recipe" is going to be a "fix" for every MCS patient.

Williams states "oxidative stress is an important determinant of what path Th1 or Th2 autoimmunity takes and Nrf2 dysfunction may determine whether disease presentation is more of a Th1 or Th2 pattern." (This is an explanation for why patients with MCS have a long list of co-morbid health conditions and why they experience such a wide spectrum of symptoms.) Most importantly his findings demonstrate as he explains,  "In this elegant study it was shown that a change in the intracellular redox status of DCs upon activation by particulates such as diesel exhaust particulates disrupt the normal ability of TLR agonists to mature DCs and this perturbation of DC function was associated with dampened IFN- and augmented IL-10 secretion in Ag-specific T cells, agreeing with these Nrf2 findings. Our data supports the idea that restoring the oxidant/antioxidant balance in DCs may have a therapeutic benefit in Th2-dominant allergic diseases. Also, enhanced activation in Nrf2-/- exposure to PM may result from decreased expression of HO-1 which is a powerful immunosuppressive" which provides evidence of loss of Treg involvement. George et al findings indeed demonstrated that Treg suppression is dependant on HO-1. HO-1 defiency leads to abolished Treg cell suppression activity normally necessary for keeping the Th1 and Th2 immune balance responses "in check" .  Interestingly it seems, the contaminant and how effective the immune response to it ultimately may determine the development of MCS and how severe the symptoms if this author and the concept of "loss of tolerance" is attributable to the condition.  As we have noted, HO-1 regulates Il-10 which is involved in Treg regulation and with the loss of IL-10 and lower levels of Tregs, heightened reactions and inflammatory responses could occur. Supportively, the author explains, "Nrf2-disrupted DCs exhibit a heightened and constitutively proinflammatory state. These observations indicate an important role for Nrf2 in gauging an appropriate pattern of inflammatory activation of DCs, key regulators of the immune response, to danger signals such as environmental particulate matter or other allergens. Disruption of the Nrf2 gene may potentially enhance host susceptibility to various allergic or infectious diseases" and this he admits, "warrants further study."

 For further reading:

• Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
• T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Williams, M. A., Rangasamy, T., Bauer, S. M., Killedar, S., Karp, M., Kensler, T. W., Yamamoto, M., Breysse, P., Biswal, S., and Georas, S. N. (2008). Disruption of the transcription factor nrf2 promotes pro-oxidative dendritic cells that stimulate th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol, 181(7):4545-4559. http://www.citeulike.org/user/HEIRS/article/3716629?show_msg=already_posted
Vojdani, A. and Lambert, J. (2009). A gut feeling for immune dysregulation & neuroinflammation in autism. http://www.citeulike.org/user/HEIRS/article/6498182
Definition of Dendritic Cell. MedicineNet.com. Retrieved January 7, 2009.
George, J. F., Braun, A., Brusko, T. M., Joseph, R., Bolisetty, S., Wasserfall, C. H., Atkinson, M. A., Agarwal, A., and Kapturczak, M. H. (2008). Suppression by cd4+cd25+ regulatory t cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol, 173(1):154-160 http://www.citeulike.org/user/HEIRS/article/6477829?show_msg=already_posted
Ibrahim, S. A. and Khalifa, N. A. (2009). Interleukin-18 correlates with disease severity in chronic autoimmune urticaria. Egyptian Dermatology Online Journal, 5(1). http://www.citeulike.org/user/HEIRS/article/6509891
Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529. http://www.citeulike.org/group/6096/article/6496762
Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., Caccamo, M., Oukka, M., and Weiner, H. L. (2008). Control of treg and th17 cell differentiation by the aryl hydrocarbon receptor. Nature, 453(7191):65-71. http://www.citeulike.org/group/5070/article/2578286

T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Over the past several months there has been a number of studies that shed light on the activities of a subset of immune cells called regulatory T-cells. Interestingly, these new findings may result in answering some important questions related to multiple chemical sensitivity which is a condition where patients become sensitive to agents normally found in the environment and these agents can be "natural" or manmade. Every MCS patient is different but their symptoms may include nausea, vertigo, brain fog, light sensitivity and others. Generally, reactions occur when MCS patients are exposed to concentrations of noxious stimulants, chemical agents or irritants that would not normally elicit a reaction in those without MCS. While there are many theories out there about what causes MCS, so far there are few that actually come close to understanding MCS and other facets of environmental illness. Unfortunately, many health experts are critical about the existence of MCS and try to classify it as a "psychomatic condition" while others are more open-minded and have begun to rally and now treat multiple chemical sensitivity as a "real" medical condition.

One MCS theory that is gaining in popularity and research support is that MCS is a condition that may be caused from a loss of tolerance and is similar in nature to inflammatory diseases that are commonly classified as autoimmune diseases. In this realm, there is no doubt that MCS could fit and recent studies provide more evidence that this could be the case. As we have noted all along several biological sub-systems, for lack of a better word, may play a part in the development of MCS and this kind of loss of tolerance or loss of homeostasis. The most recent findings support our belief that the development of MCS can be dependant on the dysregulation of Nrf2 which regulates a number of antioxidant proteins including HO-1 and NRF1 which is important for mitochondrial biogenesis. Over the past two years, we have discussed the function of this antioxidant system in modulating inflammatory cytokines. Also, important findings of vitamin D show it may be an important regulator and for MCS, it may be an important as a MCS therapy. Mainly because vitamin D can regulate regulatory Tcells and reduce autoimmune Th1 responses in association with Il-10. In the past several years a number of studies have shown that members in general population are deficient in vitamin D and supplementation of vitamin D reduces the incidence of several autoimmune conditions including MS, rheumatoid arthritis and inflammatory bowel disease. Deficiencies in vitamin D also is associated with metabolic sydrome and "itch". The latter being a common symptom in a number of autoimmune conditions as well as, multiple chemical sensitivity.

Late last year an interesting study was published that provides a little more insight on how regulatory T-cells (Tregs) may influence MCS and other environmental diseases including cancer. As the author notes in the abstract, air pollution is an important contributor to the development of environmental disease including asthma, allergy and multiple chemical sensitivity. Often the former two are co-morbid in MCS patients but not always and as Micovic explains, the assault by environmental insults including VOC results in an "abnormal immune response of lymphocytic subsets." Normally, the body is able to decipher the good and bad stimuli and develop a tolerance to those that are less noxious. Recent research findings support this process is achieved through the activities of Tregs and so is the "loss of tolerance". Interestingly, this researcher found in his experiments that normal chronic exposure to an air pollutant, increases the percentage of Il-10-dependant Tregs. On the other hand, a loss of tolerance may mean a reduction of Tregs or one of its associated proteins. In scientific studies, the destruction of Treg populations cause mice to spontaneously develop a "spectrum of autoimmune disease" (Micovic) and others displayed anaphylactic-type responses. Park clarifies how production of CD4+CD25 by Il-10 production provides a protective role against lung hypersensitivity, again, to chronic exposure to environmental antigens. Activation of nociceptors has also been implicated as a factor in MCS. (Pall) It was recently demonstrated that in a mouse model of autoimmune encephalitis, TRPV1 signaling is important in modulation of IL-10 and inhibition of TNF-a and Il-1b and subsequent increases of IL-17. (Tsuji) This explains why the TRPV1 receptor has become the focus in the development of therapeutic approaches to diabetes.

Cong describes in his paper that Tregs are believed to be "central to the prevention of autoimmune and inflammatory disorders and there are many types of these regulatory immune cells that exist including CD4+CD25+, Tr1, Tr3 and vitamin D-dexamethasone induced Il-10. Notably, we are talking about only a very small number of T cells in relation to the total number of immune cells. Therefore, unless highly specialized equipment and lab techniques are used an adequate representation of this kind of CD profile is virtually non-existent or available to the typical clinical physician. If you have read some of our blogs in the past, we discuss IL-10 quite extensively in relation to Il-10 as a modulator of the severity of sickness syndrome. Sickness syndrome is marked by a variety of symptoms including changes in appetite, mood, fatigue levels, neurotransmitters, etc that ultimately result in obvious behavioral changes and usually is considered a part of "sickness" and accompanies increases in cytokine production including Il-1 and Il-6. Sickness syndrome is not exclusive of humans and has been observed in animals. In addition, Il-10 has been shown to regulate Il-17 which is a cytokine normally associated with autoimmune-type disease and deficiencies in IL-10 correlate well to increases in fatigue and other sickness type behaviors which are characteristic of many environmental illnesses. One study shows that infection-induced inflammatory mediators including NO and TNF-a by GSK-3b, which is the off-switch for Nrf2, is achieved by inhibiting Il-10. Parkinson's diseases is considered an environmental illness and alteractions in the expression of the antioxidant HO-1 and GSK-3b increases the risk for its development. (Infante)

It is now recognized that Tregs interact with one another and in a study of asthma, the loss of IL-10 fails to "induce tolerance". Also, George demonstrates that suppression of autoimmune-type inflammatory conditions by Treg CD4+CD25+ is dependant on HO-1 often regulated through Nrf2. Rockwell recently discovered that the inflammatory cytokines Il-17 and IFN-gamma in systemic lupus, an autoimmune disease, are regulated by Nrf2 in CD4+ cells. It also regulates IFN-gamma in Th1 cells. Taking this information into account, this supports the HEIRS hypothesis that the dysfunction of the Nrf2 pathway either because of genetics or other environmental factors such as malnutrition may be critical to the development of MCS, in addition to, other environmental diseases.

Recent studies have also determined that age and mental stress can decrease the levels of Tregs and therefore, this may explain why mental stress exacerbates MCS and other environmentally-induced and autoimmune diseases. (Freier) One author suggests that in the gut, Tregs work commensally with gut bacteria to prevent intestinal inflammation and reduces expression of Il-17 implicated in carcinogensis and disregulation of this system may increase the incidence of colon cancer and may play a role in other cancers as well. (Erdman) We have suggested that the aryl hydrocarbon may contribute to symptoms of MCS and indeed, some some ligands and not others interfere with Treg expression and increase Il-17. (Quintana) To make matters more complex, the presence or absence of TLR signaling (which we have discussed exhaustively in the past) in a Il-10 -/- environment may increase the likelihood of the loss of suppression of autoimmune-type complications and lead to a "loss of tolerance" with "inocuos" pathogens such as bacteria that normally reside in the ihuman tissue such as the human gut. (Gonzales-Navajas) Notably, the relationship of Tregs, Il-10 and other factors such as GSK-3b provide an explanation of why Nrf2 activators (EGCG), vitamin D, probiotics that modulate intestinal immunity have demonstrated they reduce or alter response of inflammation, oxidative stress, and aid in the reduction of symptoms to noxious agents and have been shown to reduce the incidence of diseases including cancer and boost innate immunity. Drops in Tregs have been observed in patients with CFS (although studies conflict) and others show an abnormal immune phenotype and production of inflammatory cytokines associated with the illness is consistent with our premise that symptoms in CFS may be caused by sickness syndrome. Consequently, alterations of I-10 dependant tregs provides a mechanism for the increase risk for cancer in environmental illnesses such as CFS. It is worth mentioning that when dysregulation of the Nrf2 pathway occurs any number of aberrations in profiles may appear because the pathway controls so many different efflux proteins, transporters and enzymes. Of course, the initial trigger of illness and a patient's genetics may also lead to differences in lab profiles and explain why such a wide range of stimuli including endotoxin, perfumes, odors, oils, foods, terpenes, etc may initiate a response in MCS patients.




For original document and citations.


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Recent Links Added to the HEIRS Library!

1. The inhibitory effect of ghrelin on sepsis-induced inflammation is mediated by the MAPK phosphatase-1. http://www.citeulike.org/user/HEIRS/article/6430465#
2.Weight loss, body fat mass, and leptin in Parkinson's disease. http://www.citeulike.org/user/HEIRS/article/6429319
3. High-fat diet induces apoptosis of hypothalamic neurons. http://www.citeulike.org/user/HEIRS/article/4292700
4. Cellular localization of three vesicular glutamate transporter mRNAs and proteins in rat spinal cord and dorsal root ganglia. http://www.citeulike.org/user/HEIRS/article/6429237
5. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). http://www.citeulike.org/user/HEIRS/article/2997140
6. Sympathetic premotor neurons mediating thermoregulatory functions http://www.citeulike.org/user/HEIRS/article/6429118
7. Up-regulation in expression of vesicular glutamate transporter 3 in substantia nigra but not in striatum of 6-hydroxydopamine-lesioned rats http://www.citeulike.org/user/HEIRS/article/6428977
8. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors http://www.citeulike.org/user/HEIRS/article/6428976
9. Acute and subacute chemical pneumonitis http://www.citeulike.org/user/HEIRS/article/6428868
10. Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner http://www.citeulike.org/user/HEIRS/article/6428693
11. Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3β) on the risk of Parkinson's disease http://www.citeulike.org/user/HEIRS/article/6426071
12. Nrf2 Regulates Antioxidant Gene Expression Evoked by Oxidized Phospholipids in Endothelial Cells and Murine Arteries In Vivo http://www.citeulike.org/user/HEIRS/article/6425259
13. Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells http://www.citeulike.org/user/HEIRS/article/1496816
14. Cigarette Smoking Blocks the Protective Expression of Nrf2/ARE Pathway in Peripheral Mononuclear Cells of Young Heavy Smokers Favouring Inflammation http://www.citeulike.org/user/HEIRS/article/6425199
15. Coenzyme Q10 deficiency in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardi. http://www.citeulike.org/user/HEIRS/article/6414392
16. TLR4 is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness After Ozone Inhalation http://www.citeulike.org/user/HEIRS/article/6424875

Nrf2 as a Therapeutic Target for Stroke and Neurodegeneration

Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease.

Background: Nrf2 is a regulator of the antioxidant system including the production of HO-1 that provides protection against a number of toxic insults and GSK-3b acts as an on/off switch of that system. In addition, it has been shown that GSk-3b regulates the inflammatory response of LPS endotoxin through modulation of toll receptors. TLR4 has been shown to be instrumental in initializing and maintaining neuropathic pain.

Infante, J., García-Gorostiaga, I., Sánchez-Juan, P., Sierra, M., Martín-Gurpegui, J. L., Terrazas, J., Mateo, I., Rodríguez-Rodríguez, E., Berciano, J., and Combarros, O. (2009). Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease. European Journal of Neurology, 9999(9999). http://www.citeulike.org/user/HEIRS/article/6426071


HEIRS Library Tags: GSK-3b, HO-1

Supplemental citation: Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature immunology, 6(8):777-784. http://www.citeulike.org/user/HEIRS/article/2605
Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., Patel, S. J., Crysdale, N. Y., Harrison, J. A., Maier, S. F., Rice, K. C., and Watkins, L. R. (2008). Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (tlr4). The European journal of neuroscience, 28(1):20-29. http://www.citeulike.org/user/HEIRS/article/2997140