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

Alterations of BDNF, Behavior Hormones in PTSD, Fibromyalgia and Other Environmental Illnesses

Many experts believe that the functions of the hypothalamus are dysrupted in environmental illness. We recently blogged about how hypothalamus-stimulated signaling of  BDNF levels are altered in a number of environmental illnesses. In fibromyalgia they are increased while in other are they are lower. A more recent report has indeed supported the fact that BDNF levels are increased in fibromyalgia. Also, they have demonstrated that this hormone is elevated shortly after trauma in PTSD and evens out over time. Interestingly, these findings were independant of severity, psychiatric history and treatments with medication. Because BDNF has been implicated in learning and memory the higher levels of this protein may contribute to the pathology of PTSD and considering they are elevated in fibromyalgia, one may suspect they also contribute to the pathology of fibromyalgia also. Of course, further evidence is warranted but these findings are interesting none-the-less.

Note:

• Orexin is another signaling peptide of the hypothalamus and it has been demonstrated that altered levels are consistent with fibromyalgia, chronic fatigue syndrome, PTSD and panic attacks. We have discussed this hormone in other blogs and explained, it dictates a number of different animal behaviors and is sexually dimorphic and plays a role in sickness behavior.  In addition, there is an important connection between orexins and BDNF. Dopamine are regulators of orexins and low levels are also associated with Parkinson's disease.
• BDNF is mediated by GSk-3b which is implicated in a number of psychological disorders and can be activated by environmental exposures. (Mai)

For further Reading:

• Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

Reference Library Tags: orexin, narcolepsy, chronic fatigue syndrome, PTSD, BDNF
                HEIRS Blogs: orexins, BDNF, chronic fatigue syndrome, sickness syndrome, fibromyalgia,  PTSD,


Strawn, J. R., Pyne-Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L. A., Baker, D. G., and Geracioti, T. D. (2010). Low cerebrospinal fluid and plasma orexin-a (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. http://www.citeulike.org/user/HEIRS/article/6644003
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today.  http://www.citeulike.org/user/HEIRS/article/6640584
Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., and Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. The European journal of neuroscience, 21(11):2993-3001. http://www.citeulike.org/user/HEIRS/article/6463668
Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930. http://www.citeulike.org/user/HEIRS/article/4967509
Stanley, S., Wynne, K., McGowan, B., and Bloom, S. (2005). Hormonal regulation of food intake. Physiol. Rev., 85(4):1131-1158. http://physrev.physiology.org/cgi/content/full/85/4/1131/F2
Mai, L., Jope, R. S., and Li, X. (2002). Bdnf-mediated signal transduction is modulated by gsk3β and mood stabilizing agents. Journal of Neurochemistry, 82(1):75-83. http://www.citeulike.org/user/HEIRS/article/6621876

Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

In our recent blog discussed how orexin(hypocretin) effects sleep patterns and may have an important role in CFS and sickness syndrome. A new study using a pharmaceutical called sodium oxybate showed significant improvement in patients in fatigue with both chronic fatigue syndrome and fibromyalgia and point to the "real possibility" that sleep problems in these conditions are similar to narcolepsy. In addition, the study suggests, even though further study is warranted that both CFS and FM are similar or not the same condition because of the improvements seen in patients with them.  We have noted similarities to sickness syndrome in these conditions and have emphasized that sickness syndrome also occurs in animals and importantly, narcolepsy also is not exclusive to humans and in often seen in dogs. Some breeds more commonly than others.

Other recent discoveries indicate that the major pathophysiology of human narcolepsy "is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient." Narcolepsy is thought to be an autoimmune related disorder and can alter regulation of cortisol and influence steroid production which also may initiate panic.  In our recent blog, we wrote how streptococcus pneumoniae may be an important trigger of orexin-influenced narcoleptic sleep behavior. This is important because this pathogen effects the severity of H1N1 and may mean that patients with EI may be more susceptible to both. Parkinsonism is also associated with alterations in hypocretin and future therapies in PD may involve treatments involving orexin. Some suggest that narcolepsy and Parkinson's disease have a common and therefore, one must begin to hypothesize that CFS and fibromyalgia may have the same or similar causal factors as PD and and narcolepsy.

For Further Reading About Orexins in CFS, Sickness Syndrome and Fibromyalgia, see

• How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome. HEIRS, January 1, 2010.
• Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

Spitzer, A. R. and Broadman, M. (2010). Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate. Pain Practice, 10(1):54-59. http://www.citeulike.org/user/HEIRS/article/6512085
Zeitzera, J. M., Nishinob, S., and Mignotc, E. (2006). The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends in Pharmacological Sciences, (27):368-374. http://www.citeulike.org/user/HEIRS/article/6512089
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today. http://www.citeulike.org/user/HEIRS/article/6512132

How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome.

Background: Many research experts believe that endotoxin is a causal factor in the development of chronic fatigue syndrome. (Maes) In addition and as we have discussed on this blog, many of the symptoms may be attributed to sickness behavior or sickness syndrome. Generally, this is regarded as a reflection of immune responses that alter normal functions of hormones, neurotransmitters, etc. resulting in changes in behavior in humans and other animals.

We recently discussed how dysregulation of the hormone, ghrelin, may effect sickness behavior. A study just published provides more details about how another hormone may contribute to sickness syndrome and related alterations in behavior. According to the study, LPS endotoxin suppresses the neuronal circuitry in orexin and histamine neurons. As the abstract describes, the orexin neurons in the brain are important for behaviors including waking, feeding and reward-related behaviors and can be regulated by dopamine (Bubser), provide antinociceptive protection (Mobarakeh) and may reduce gastrointestinal injury through several mechanisms including injury from TLR signaling. In other blogs, we describe in detail how LPS from gram-negative bacteria and other environmental contaminants such as ozone can initiate inflammatory effects through TLR signaling and that genetic or environmental dysruption of the Nrf2 system will enhance the inflammatory effects.

Outside the brain, orexin neurons stimulate the production of cortisol in the adrenal glands and another studies shows orexin can time-dependantly raise cortisol levels as well as, influence steroidogenesis. Orexin studies have also revealed it regulates histamine release in the brain. Interestingly, narcolepsy which is suspected to be an autoimmune-related condition is associated with orexin deficiency. Aran proposes that streptococcus is an environmental trigger of narcolepsy. For this reason, the results of these studies in combination suggest that both gram-negative and gram-positive bacteria may contribute to sickness syndrome by altering orexin levels. In addition, orexin is a sexually-dimorphically expressed hormone which may help to explain the gender differences in the rates of environmental illness. (Johren)

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Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

CiteULike: Lipopolysaccharide challenge-induced suppression of Fos in hypothalamic orexin neurons: their potential role in sickness behavior.: "Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930."

Runaway vigilance hormone linked to panic attacks. National Institute of Mental Health. http://www.citeulike.org/user/HEIRS/article/6463151

CiteULike: Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (Zonotrichia leucophrys).

CiteULike: Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (Zonotrichia leucophrys).: "Owen-Ashley, N. T., Hasselquist, D., Råberg, L., and Wingfield, J. C. (2008). Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (zonotrichia leucophrys). Brain, behavior, and immunity, 22(4):614-625."

Sickness behaviour pushed too far - the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma

CiteULike: Sickness behaviour pushed too far - the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma: "Clark, I., Budd, A., and Alleva, L. (2008). Sickness behaviour pushed too far - the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma. Malaria Journal, 7(1):208+."

Attenuation of the influenza virus sickness behavior in mice deficient in toll-like receptor 3. Brain, behavior, and immunity.

"Certain sickness behaviors occur consistently in influenza-infected humans and mice. These include body temperature changes, somnolence, and anorexia..... Therefore virus-associated dsRNA detected by TLR3 appears to play a substantial role in mediating several aspects of the influenza syndrome in mice."

Majde, J. A., Kapás, L., Bohnet, S. G., De, A., and Krueger, J. M. (2009). Attenuation of the influenza virus sickness behavior in mice deficient in toll-like receptor 3. Brain, behavior, and immunity. http://www.citeulike.org/user/HEIRS/article/6048823

Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Toll-like receptors: are a class of proteins that play a key role in the innate immune system. (Wipedia)

Background: Binding to toll-like receptors may initiate inflammatory responses including the production of chemokines. They mainly signal through NF-kappaB and increase transcription of inflammatory proteins Il-1b, Tnf-a, CCL2 (MCP-1) etc. (Devaraj) These are receptors that are highly expressed and are considered to be a link between diet and metabolism and are implicated as important factors in a number of health conditions including lupus, atherosclerosis and diabetes. (Dasu) We have noted in other blogs that they may play an important role in conditions that are most often considered "environmental illnesses" including chronic fatigue syndrome and/or contribute to symptoms of chemical sensitivity. To put it simply, toll-like receptors are considered signal transducers that initiate inflammatory processes and two common ligands are LPS endotoxin (which has been implicated in CFS) and saturated fatty acids. The ligands that bind TLR contain a "molecular pattern" the TLR recognizes and may be present in microbial and non-microbial agents or may be responsive to signals generated at the site of inflammation or from endogenously-produced proteins like heat shock proteins. Thus, their activites become a concern when ever pathogenic exposure or inflammation may be present.

The distribution of the toll-like receptors is different in different tissues but include epithelia and endothelia in the intestinal tract, the respiratory tract, the blood-brain barrier, etc. It is now believed that there is a commensal relationship that exists between the gut microbiota and TLR to maintain gut integrity (Hopkins) and may involve epigenetic influences and down-regulation of TLR gene transcription. (Takahashi)    It has been determined that TLR2 and TLR4 bind to gram positive and negative bacteria respectively. However, the production of one type of TL receptor may induce the induction of the other. Devaraj demonstrated that type-1 diabetes and increased levels of IL-1b and TNF-a is correlated with expression of TLR and also endotoxin "contribute to the inflammatory burden by activating TLR receptors" and suggests their instrumental in diabetes pathology. In addition, it has also been determined that high glucose levels can stimulate the expression of these receptors in monocytes. While toll-like cells are involved in cytokine production and cell activation, the inflammatory responses initiated by activation of receptors may last long after the initial stimulus is gone or may potentiate the inflammatory responses of other insults. It may seem beneficial to blunt the responses of TLR, but it may be more harmful by making the organism more susceptible to infection.(Hopkins) On the other hand, aberrant signaling from TLR can lead to autoimmune-type conditions as we noted above.

Other studies demonstrate that the expression of TLR are widespread are can activate microglia and astocytes and play a role in neuroinflammatory responses. Microglia are sensory-type cells that are the main source of inflammatory mediators in the nervous system.  Some studies show that TLR activation of microglia leads to an increase in NO, superoxide and other cytokines and that TLR-deficient microglia demonstrated a significant reduction in several types of inflammatory responses. Obata confirmed TLR3 has an important role in the development of tactile allodynia after nerve injury and blocking these receptors may provide effective treatment for neuropathic pain which has been linked to fibromyalgia. Recent findings are suggestive of the notion that fibromyalgia is a "disorder of central processing with neuroregulation/
transmission dysfunction" (NFA) and TLR4 may initiate an inflammatory profile through NF-kappaB at least in a subset of fibromyalgia patients. In one model of neuropathic pain, tactile allodynia was "abrogated" in CCR2 mice which is the receptor for CCL2 (MCP-1), the inflammatory cytokines activated by NF-kappaB and has been suggested as a possible marker for fibromyalgia. It also plays a very important role in the development of neuroinflammation via the TNF-a/CCL2/CCR2 pathway. From this, it has been suggested that activation of immune cells and microglia peripherally and in neurons may contribute to inflammatory and neuropathic pain states and (Abbadie) importantly, it is now understood that TLR agonists modulates CCR2 expression and CCL2 responsiveness. (Souto, Parker) Jo et al explains peripheral injuries that lead to neuropathic states causes pathology not only in the damaged nerves but also causes changes in the central processing of sensory information and glial activation may facilitate "noxious signal transduction" even after the initial injury has healed. Therefore, TLR may not only initiate neuropathic pain but also maintain it.  Experts believe nociceptive behavior may influence symptoms of MCS (Pall) and it has been demonstrated pain caused by bacterial infection may be generated through activation of nociceptors via the TLR in neurons. (Wabachi) In addition, TLR responses play a role in viral and parasitic infections, multiple sclerosis, exacerbate injury in ischemia (Kielian) and chronic activation of TLR is associated with anxiety, avoidance and sickness behavior (Hudson) and increased sensitivity to other toxicants (Pestka).

Other reports show in epithelial cells, TLR mediate immune cells production from exposure to particulate matter and contribute to airway hypersensitivity from exposure to ozone. (Williams) More recently, it has been shown that the aryl hydrocarbon receptor (AhR), which plays a role in the detoxification of polyaromatic hydrocarbons and halogenated hydrocarbons, negatively regulates TLR signaling. Animals that are deficient in the AhR exhibit exaggerated inflammatory responses including significant elevations in TNF-a and IL-6 and are highly susceptible to septic shock. (Ogawa, Kimura) We have expressed the belief that the abnormal functioning of the AhR may contribute to environmental illnesses including multiple chemical sensitivity because of its role in detoxification and its relationship to the antioxidant system regulator Nrf2. The Nrf2 protects neurons and other cells against oxidative and environmental insults in primary and secondary injury. TLR activates NF-kappaB through the universale adaptor protein MyD88 and it has been shown that Nrf2 has a "global influence" on MyD88-dependant and independant signaling. Deficiency of Nrf2 dysregulated expression of genes that encode molecular components of innate immunity (e.g., peptidoglycan-recognition proteins, proinflammatory cytokines, chemokines, and adhesion molecules and receptors." (Thimmulappa)

Study Highlight: Pestka provides evidence that the preexposure of a TLR agonist such as LPS endotoxin increases the inflammatory response of DON, a mycotoxin. This response which included production of IL-1b, Il-6, and TNF-a was at levels higher than either produced alone. During the study, preexposure to other TLR agonists, also increased the pro-inflammatory responses of DON in a similar manner as LPS. In addition, similar heightened responses occured from LPS preexposure of TLR and subsequent effects of microbial and non-microbial "agents" including satratoxin, Shiga toxin, zearalenone and toxicants such as nickel chloride, triphenyltin, dinitrochlorobenzene (a known irritant) and dioxin. It has been concluded from this study that prior exposure to TLR agonists (ie endotoxin, saturated fat and others) "might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action." (Pestka)

Notes:

• An important source of bacterial and endotoxin contamination is from our drinking water. Find out more about the importance of healthy water with a clip from the Dr. Oz Show. Other main sources include from the air we breath.
• IRAK-1 is necessary for LPS-mediated suppression of PPARalpha and PGC-1alpha, nuclear factors essential for the expression of anti-oxidative enzymes such as GPX3 and catalase (Maitra) "ROS trafficking(NADPH oxidase) mediates LPS/TLR signals in neutraphils and downstream targets including IRAK-1. Deficiency of Nrf2 predisposes neutraphils to greater responsiveness to LPS which is mediated by increased ROS generation. (Thimmulappa)

Reference Resource:

• Toll-like receptor (TLR)-mediated biology (Hopkins)
  

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Exercise and Fatigue

During exercise skeletal muscle produces Il-6 which tends to inhibit the production of Tnf-a and Il-1b which are two factors that contribute to the development of sickness syndrome.


Wood, L. J., Nail, L. M., and Winters, K. A. (2009). Does muscle-derived interleukin-6 mediate some of the beneficial effects of exercise on cancer treatment-related fatigue? Oncology nursing forum, 36(5):519-524. http://www.citeulike.org/user/HEIRS/article/5727478

Green Tea Protects Skin From UVB Radiation!

Definition: Dendritic cells (DC) are immune cells that take antigen and present it to other immune cells. They are present in tissue that have direct access to the external environment including the skin, nose, stomach, lungs and intestines. They possess cell-to-cell type interaction which includes communication with cytokines. Wipedia describes one example of their action includes when microbes stimulate antigens to produce IL-12 which primes the immune system for attack on antigens that DCs present. (Wipedia)

Background: Epigallcatechin gallate (EGCG) is a substance found in high amounts in green tea. It has recently been shown in studies to have benefit on the symptoms related to a mouse model of chronic fatigue. (Sachdeva)

Title: Protective effect of epigallocatechin gallate on the immune function of dendritic cells after ultraviolet b irradiation.

Summary: EGCG counteracts the inhibitory effect of UVB radiation on the immune properties of dendritic cells. It was shown in this study to down-regulate the secretion of IL-12 and up-regulates Il-10. The former Il-12 can stimulate the production of Tnf-a and IFN-gamma and is associated with autoimmune disease. The latter has an important role in modulating sickness syndrome.

Citations:

Jin, S. L., Zhou, B. R., and Luo, D. (2009). Protective effect of epigallocatechin gallate on the immune function of dendritic cells after ultraviolet b irradiation. Journal of Cosmetic Dermatology, 8(3):174-180. http://www.citeulike.org/user/HEIRS/article/5700567

Sachdeva, A. K. K., Kuhad, A., Tiwari, V., and Chopra, K. (2009). Epigallocatechin gallate ameliorates chronic fatigue syndrome in mice: Behavioral and biochemical evidence. Behavioural brain research. http://www.citeulike.org/user/HEIRS/article/5323625

Resource:

• Gourmet tea, coffee and gifts.

CFS, Probiotics and Il-10

HEIRS Environmental Illness Research Blog: Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

Probiotics have been shown to be effective to relieve some of the behvioral effects of chronic fatigue syndrome. Ng explains that one of their modes of action is the ability to reduce inflammation. This is true in animals that are negative for Il-10 which as we noted regulates the severity of sickness syndrome according to some studies. He explains for example, Lactobacillus is able to improve barrier functions in vivo.

Ng, S. C., Hart, A. L., Kamm, M. A., Stagg, A. J., and Knight, S. C. (2009). Mechanisms of action of probiotics: Recent advances. Inflammatory Bowel Disease, 15(2). http://www.citeulike.org/user/HEIRS/article/5701960

Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

A study that was published last year suggested that MCP-1/CCL2/CCr2 and eotaxin may be good biomarkers for fibromyalgia and identify a genetic component to the condition. (Zhang) Since then, researchers have noted that both chronic fatigue syndrome and fibromyalgia may be classified as inflammatory conditions when the exact cause of symptoms is not known. Interestingly, MCP-1 can cause inflammatory responses and therefore has the potential of contributing to sickness behavior syndrome which is a condition that results in behaviors often associated with people that are ill. Sickness behavior does not seem exclusive of human beings because similar behaviors have been observed in other animals. Maes concludes that oxidative and nitrosative stress contribute to the development of chronic fatigue which result in an increase inflammation, NF-kappaB, COX2, iNOS and damage to lipids and proteins. He further explains that triggers include strenuous exercise, LPS from gram negative bacteria, viruses and pshycological or physical stress. A few of the symtoms associated with sickness syndrome include fatigue, malaise, appetite changes, anxiety, depression, weight changes, sleep alterations and numerous others. (Maes) Previous studies show it can be stimulated by a variety of conditions including IGF-1, Tnf-a and Il-1b the latter two are produced as part of the stress response and modulated by the Nrf2 system that also stimulates induction of antioxidants. (Dantzer) Nrf2 has been shown to modulate metabolic homeostasis in adipocytes and is now linked with obesity. Nrf2 is responsible for detoxification of electrophiles and xenobiotics and the function of it can be altered by any number of environmental factors including but not limited to metals, nutrition, and other protein interactions such as the AhR which also may play a very important role in chemical sensitivity.

The severity of sickness syndrome has been demonstrated to be determined on the prevalence of the anti-inflammatory immune complex IL-10. When it is present the duration of sickness syndrome is less and the effects like memory and learning impairment are also decreased. (Richwine) Il-10 has been shown to reduce the levels of IFN-gamma and Tnf-a- induced production of superoxide and nadph oxidase 1 (NOX1) which would suggest prevention of ROS generation from it. (Kamizota) Il-10 also stimulates the induction of HO-1 and therefore may activate the Nrf2 pathway but HO-1 can act independantly. Inhibition of HO-1 significantly reduces the protective effects of Il-10 on Tnf-a by LPS. Lee et al shows that this relationship also involves carbon monoxide, a gasoneurotransmitter, on the protective effects of Il-10. Therefore this further suggests a possible involvement of Nrf2 considering that Nrf2 modulates the effects of carbon monoxide. (Lee) De Wilde demonstrated that production of Il-10 is completely abolished with inhibition of HO-1.

Nrf2 is now associated with protective effects in adipocytes. Eotaxin is a chemokine that is elevated in obesity because adipose tissue seems to be the predominant source of it. It is also an important inhibitor of MCP-1 and is a common factor in allergic reactions. Its presence at the site of allergic inflammation suggests coordinated cellular responses of allergic inflammation where both MCP-1 and eotaxin are present. (Olgilvie) Tnf-a is overexpressed in obesity (Uysal) and associated with insulin resistance and inhibition of the expression of numerous genes including PPAR-gamma and adiponectin. It is also an important inducer for prolonging the half-life of eotaxin.

Summary:

• Maes has suggested that a pathway to chronic fatigue syndrome is by LPS endotoxin and therefore because the production of Il-10 modulates the severity of sickness syndrome through HO-1. We can suggest that the alteration in signaling of Nrf2 could ultimately lead to CFS and sickness syndrome.
• Nrf2 is conserved in different organisms, the homolog in C elegans is skn-1. (An)
• Nrf2 can be ethnically derived and therefore some populations may be more susceptible to some of the triggers and have an increased risk for chronic fatigue syndrome. (Marzec, Dinos)
• EGCG has been shown to have positive effects on chronic fatigue syndrome in a mouse model of CFS. Studies have shown that EGCG increases induction of HO-1 through Nrf2.
  

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