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

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

Chronic Fatigue, Insulin Resistance, Il-10 and Sickness Syndrome

Definition:

• Bioaccumulation: refers to the accumulation of substances, such as pesticides, or other organic chemicals in an organism. (Wipedia)

Background: Several months ago we discussed an article the describes the results of a study that revealed a link between accumulation of chemicals and diabetes. That study also noted the relationship was correlated to a higher incidence of obesity. In addition, we have recently described that Nrf2 plays a homeostatic role in adipocytes it now appears Nrf2 plays a modulatory role in adipogenesis and when the Nrf2 activity is impaired there is a greater risk for obesity. We have also discussed at length that chemicals bioaccumulate in fat tissue where they produce inflammatory mediators and decrease regulatory and anti-inflammatory proteins such as PPAR-gamma (which when overregulated can contribute to obesity) and adiponectin and it is assumed now this is also true because high-fat diets may impair Nrf2 which influences the control of inflammatory responses mediators such as Tnf-a and MCP-1/CCL2/CCR2, may prevent or delay activation of the antioxidant system. Nrf2 also is responsible for gene expression for proteins important for mitochondrial respiration such as NRF1 and PPAR-a. The latter being a regulatory factor that cooperates with PGC-1a during mitochondrial biogenesis. Insulin resistance also impairs mitochondrial function and is quite a common characteristic that leads to diabetes and obesity.

Other important things we have noted recently are:

• 
  Sickness syndrome includes a number of behavioral symptoms including fatigue, malaise, increased sensitivity to pain, loss of appetite, anxiety, depression and numerous other symptoms. A recent study has demonstrated that the severity of sickness syndrome depends on the presence or absence of IL-10. If it is present the shorter and less severe the symptoms and if it is absent the patient will experience more severe pathology. In addition, we also noted that MCP-1 is activated by Tnf-a and IL-6 in peripheral tissue to caused neurotransmission in the brain that can incite the inflammatory cascade.
• We also noted that Il-10 is regulated by HO-1 which also is regulated by Nrf2. If the Nrf2 pathway is impaired or inhibited in adipocytes, there is greater opportunity for an elevated inflammatory response in those tissues and the body would have a reduced ability to detoxify an "bioaccumulating" agent that it might be exposed to such as pesticides and other environmental contaminants.
• We have also noted the Nrf2 system can be impaired by exposures to metals, aging factors, other genetic factors, hyperglycemia which is now considered a consequence of environmental or endogenous exposures (H2S).
• 
  
  The Nrf2 regulates and is regulated by the aryl hydrocarbon that mediates the detoxification of PAHs and HAHS including dioxin and ingredients in agricultural products. The toxicity of dioxin is mediated through the AhR and is abnormal function may have an extremely important role in toxicity of endotoxin which Maes describes as a pathway to the development of CFS.

A new study has revealed more important details about Il-10 that sheds more light on the symptoms associated with sickness behavior and chronic fatigue syndrome. This new study demonstrates that Il-10 is important for maintaining insulin sensitivity by protecting muscles from obesity-associated macrophage infiltration of inflammatory cytokines and diet-induced inflammatory responses. In the study, it was shown these cytokines include Tnf-a, Il-6, and CCR2. These are markers important in findings related to CFS and fibromyalgia and other environmental illnesses and develop (You can read about MCP-1 here) as part of the stress response from toxicant insults. This study indicates not only that IL-10 may be used as therapy for diabetes but one can suggest future therapies may also target environment illnesses that have presentations of fatigue, muscular pain and sensitivity. A past study demonstrated that Il-10 prevented alterations in Il-6 hepatic insulin action, signaling, and also Il-6 and lipid-induced insulin signaling in skeletal muscle and therefore support the findings from the study noted above. (Kim) Both studies provides evidence of an important role of Nrf2 in regulating metabolic homeostasis by regulating HO-1/IL-10 and demonstrates how its impairment or inhibition can lead to environmental illness.

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.
  

All rights reserved.

Source Citations