TLRs Interaction W/ Pathogens Can Increase Resistance From Host Immune Defense.

"A special set of sugars found on some disease-causing pathogens helps those pathogens fight the body's natural defenses as well as vaccines, say two Iowa State University researchers"

Read more: Cause Of Immune System Avoidance Of Certain Pathogens: Discovery By ISU Researchers:

Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice.

CiteULike: Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice.: "systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies."

TLRs Regulates Reactions to Particulate Matter and Other Contaminant Considerations~!

In this article, the author explains "it is plausible that PM2.5 contains bacterial or mycoplasma lipoproteins, which are known activators of TLR2 . Because PM2.5 contain high concentrations of a large number of metals. One or more of these metals could be involved in increased TLR2- mediated cytokine production triggered by microbial lipoprotein constituents of the PM2.5. In this regard, it is interesting that TLR2 has been implicated in proinflammatory cytokine expression by airway epithelial cells stimulated with air PM containing high amounts of metals. Another possibility is that PM2.5 cytokine-inducing effects are mediated by an indirect mechanism, via the generation of endogenous “danger” host molecules activating macrophages via TLR2."

Note: Recent findings by Notch show a potentiation effect between cyanobacteria and heavy metals and thus support an important mechanism although the mechanism remains to be elicited. In addition, one must always consider alterations in methylation which can be caused by endotoxin and heavy metals. Walsh and Usman demonstrated that in autism there is alterations in the functioning of metallotheinin protein which modulates and detoxifies metals. (Treat Autism and AD/HD, Wright) In other blogs, we have explained that metallotheinin inhibits GSK-3b (Wang)which can turn off the Nrf2 antioxidant system. This could explain why there are reports that the antioxidant system is negatively effected by metals (and by endotoxin)and thus, one must also consider that in mixed environmental pollutants, there is a reduction of function of this system. In addition, there is also potential that the AhR and metals interact to influence antioxidant and detoxification. These interactions of metals and the AhR are currently being investigated through a number of projects. (Korashy) Further study may shed more light on the interactions of the Nrf2 and AhR gene batteries and how they are effected by metals from environmental exposures.

Shoenfelt, J., Mitkus, R. J., Zeisler, R., Spatz, R. O., Powell, J., Fenton, M. J., Squibb, K. A., and Medvedev, A. E. (2009). Involvement of tlr2 and tlr4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter. Journal of Leukocyte Biology, 86. http://www.citeulike.org/user/HEIRS/article/7367529

Vita. Hesham Korashy, PhD. Retrieved on June 29, 2010.
http://faculty.ksu.edu.sa/hkorashy/Pages/index.aspx

Notch, E. G., Miniutti, D. M., Berry, J. P., and Mayer, G. D. (2010). Cyanobacterial lps potentiates cadmium toxicity in zebrafish (danio rerio) embryos. Environmental toxicology.
http://www.citeulike.org/user/HEIRS/article/7367622

Heavy Metals. Treat Autism and ADHD. Retrieved on June 30, 2010. http://www.treatautism.ca/?page_id=126

Wang et al. Inactivation of GSK-3 by Metallothionein PreventsDiabetes-Related Changes in Cardiac EnergyMetabolism, Inflammation, Nitrosative Damage, and Remodeling. Diabetes. June 2009. Pgs. 1391-1402.

Wright, R. O. and Baccarelli, A. (2007). Metals and neurotoxicology. The Journal of Nutrition.
http://www.citeulike.org/user/HEIRS/article/7367642

Absence of TLR2 Protect Against Insulin Resistace from High Fat Diet~!

According to the author, this study presents evidence TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.

HEIRS Health Research Blog: Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2

Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2

In this study, we tested the hypothesis that HSV-induced neural cell oxidative tissue damage and cytotoxicity are mediated by microglial cell ROS through a TLR2-dependent mechanism. We detected elevated intracellular ROS in HSV-infected microglia obtained from wild-type mice. In contrast, the virus failed to induce ROS in microglia obtained from TLR2-/- mice. Additionally, compared to wild-type microglia, TLR2-/- microglia displayed attenuated HSV-induced lipid peroxidation and neurotoxicity. These studies demonstrate the importance of microglial cell TLR2 in inducing oxidative stress and neuronal damage in response to viral infection.

CiteULike: Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2: "Schachtele, S., Hu, S., Little, M., and Lokensgard, J. (2010). Herpes simplex virus induces neural oxidative damage via microglial cell toll-like receptor-2. Journal of Neuroinflammation, 7(1):35+."

Note: If high fat diets (HFD) influence the expression of TLR2 - one could assume that HFD may augment inflammatory responses. Diets that are lower in fat such as a typical Mediterranean Diet may reduce these inflammatory mediators and reduce symptoms. Other studies show that high glucose diets may also induce TLR expression (Dasu) and there is evidence that TR2 is necessary for development of the metabolic syndrome which makes one at higher risk for cardiovascular disease and diabetes (Himes).

For Further Reading: ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!

HEIRS Library Tags: TLR2


Dasu, M. R., Devaraj, S., Zhao, L., Hwang, D. H., and Jialal, I. (2008). High glucose induces toll-like receptor expression in human monocytes. Diabetes, 57(11):3090-3098.
http://www.citeulike.org/user/HEIRS/article/3207456
Himes, R. W. and Smith, C. W. (2009). Tlr2 is critical for diet-induced metabolic syndrome in a murine model. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology.
http://www.citeulike.org/user/HEIRS/article/6002948
Schachtele, S., Hu, S., Little, M., and Lokensgard, J. (2010). Herpes simplex virus induces neural oxidative damage via microglial cell toll-like receptor-2. Journal of Neuroinflammation, 7(1):35+.
http://www.citeulike.org/user/HEIRS/article/7366356
Lee, J. Y., Zhao, L., Youn, H. S., Weatherill, A. R., Tapping, R., Feng, L., Lee, W. H., Fitzgerald, K. A., and Hwang, D. H. (2004). Saturated fatty acid activates but polyunsaturated fatty acid inhibits toll-like receptor 2 dimerized with toll-like receptor 6 or 1. The Journal of biological chemistry, 279(17):16971-16979.
http://www.citeulike.org/user/HEIRS/article/3328606

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."

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

Carbon monoxide differentially inhibits tlr signaling pathways by regulating ros-induced trafficking of tlrs to lipid rafts.

HEIRS Environmental Illness Research Blog: Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Nakahira, K., Kim, H. P., Geng, X. H., Nakao, A., Wang, X., Murase, N., Drain, P. F., Wang, X., Sasidhar, M., Nabel, E. G., Takahashi, T., Lukacs, N. W., Ryter, S. W., Morita, K., and Choi, A. M. K. (2006). Carbon monoxide differentially inhibits tlr signaling pathways by regulating ros-induced trafficking of tlrs to lipid rafts. J. Exp. Med., 203(10):2377-2389. http://www.citeulike.org/user/HEIRS/article/6013733



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Microbial induction of IBD Through Protein Expression By TLR Signaling

HEIRS Environmental Illness Research Blog: Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!


Summary: A number of gram negative, gram positive and other anaerobes stimulate protein that contributes to IBD. This process is dependant on TLR signaling and can be inhibited by blocking the P38 pathway. In an earlier study showed that the levels of TL1A and number of cells that expressed it correlated with the level of inflammation, especially in Crohn's disease.

Title:Microbial induction of inflammatory bowel disease associated gene tl1a (tnfsf15) in antigen presenting cells.
Shih, D. Q., Kwan, L. Y., Chavez, V., Cohavy, O., Gonsky, R., Chang, E. Y., Chang, C., Elson, C. O., and Targan, S. R. (2009). Microbial induction of inflammatory bowel disease associated gene tl1a (tnfsf15) in antigen presenting cells. European Journal of Immunology, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/6009014
Bamias, G., Martin, C., Marini, M., Hoang, S., Mishina, M., Ross, W. G., Sachedina, M. A., Friel, C. M., Mize, J., Bickston, S. J., Pizarro, T. T., Wei, P., and Cominelli, F. (2003). Expression, localization, and functional activity of tl1a, a novel th1-polarizing cytokine in inflammatory bowel disease. Journal of immunology (Baltimore, Md. : 1950), 171(9):4868-4874. http://www.citeulike.org/user/HEIRS/article/6009138

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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Original document and citations can be accessed here.

Fats Interact With Immune Complex to Activate Inflammation -May Aggravate Autoimmune and Pathogen Infection

HEIRS Environmental Illness Research Blog: Infection/Endotoxin in Chronic Fatigue, Fibromyalgia and Multiple Chemical Sensitivity.

The interaction between toll-like receptors and fatty acids "engage" the immune complex Il-1b and its receptor to activate other inflammatory processes in the pancreas.



Böni-Schnetzler, M., Boller, S., Debray, S., Bouzakri, K., Meier, D. T., Prazak, R., Kerr-Conte, J., Pattou, F., Ehses, J. A., Schuit, F. C., and Donath, M. Y. (2009). Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor i. Endocrinology, pages en.2009-0543+. http://www.citeulike.org/user/HEIRS/article/5922922

Infection/Endotoxin in Chronic Fatigue, Fibromyalgia and Multiple Chemical Sensitivity.

Definition: Endotoxin: a toxic component of bacteria not excreted by live bacteria but induces the inflammatory cascade and production of NO. (Endotoxin)

 An increasing number of scientific publications support the hypothesis that endotoxin infection and sickness syndrome may be important factors in environmental illnesses including fibromyalgia, chronic fatigue syndrome and quite possibly MCS. In fact, sickness syndrome would be a reasonable and holistic approach for explaining many of the behavioral, physical and emotional complications that are common in environmental illness. Sickness syndrome is described as the presence of a variety of symptoms including malaise, fatigue, sleep disturbances, appetite changes, brain inflammation, mood changes such as anxiety and depression and a host of other symptoms that occur as a reponse to injury or infection.  These responses occur both in humans and animals and some propose it is in part, adapative responses that are generated to alter the responses of the host and their social network. Over the past several years, there has been an significant amount of research on sickness syndrome. The occurence of which can be attributed to inflammatory cytokines that alter neurotransmission and genetic expression. There have been studies that show altered gene expression in environmental illnesses; the consequences of which can be quite severe and unexpected. Il-10 is an anti-inflammatory cytokine that has been shown to modulate the severity of sickness syndrome through interaction with HO-1. HO-1 is also a cytokine that is induced by activation of Nrf2, although there are other pathways that can induce this antioxidant. Recently, it has been demonstrated that the protective effect of an endogenous peptide thryotropin, against the damaging effect on the dopamine system from paraquat, is due to the chemicals ability to activate Nrf2 to reduce reactive species and increase the antioxidant glutathione. Other studies have demonstrated that thyrotropin is able to reverse hyperglycemia by increasing beta cell function and reducing programmed cell death. (Luo) Insulin resistance and diabetes are suspected to be important consequences of the sustained presence of inflammation and inflammatory cyokines that are characteristic of environmental illnesses.

A recent published study showed that there is brain disfunction in multiple chemical sensitivity (Orriols) and last week I suggested that some of the cognitive effects could be from an altered expression of BDNF. Of course, there are any number of factors such as malnutrition and inflammation that can influence cognitive function. Neurotransmitter regulate and can alter cognition and are modulated by factors that produce "sickness syndrome".  According to the author of the recent MCS study, SPECT scans showed alterations in the regions of the brain including the cingulus, striatum and the hippocampus in addition to others. Pekary et al explains that a common environmental toxin LPS has the potential to alter the expression of thyrotropin which may have an impact on LPS toxicity. The study showed elevations of cytokines and corticosterone after LPS with a transient drop in T3. Other results showed a decrease in thyrotropin-releasing hormone in certain areas of the brain while increasing it in others. Thyrotropin has been shown to improve recovery after neurological dysfunctions such as brain trauma and epilepsy in humans and animals and be neuroprotective against NMDA neurotoxicity. (Pizzi) These regions the author noted are areas that are associated with the neuroimmunomodulatory effects of sickness and injury and danger and appear to be similar to those effected in MCS SPECT scans. Also, a sustained elevation in TRH was present in b-cells accompanied by LPS-impaired insulin secretion. From these findings, the author concluded that thyrotropins can mediate and moderate the behavioral and toxic effects of LPS. In addition, LPS elevates inflammatory cytokines including Tnf-a, Il-6 and Il-1b and also increases expression of TLR receptors 2 and 4 and causes a prolonged sickness behavior in aged animals. Taking these findings into account and the fact that thryotropin mediate their positive effects through Nrf2, then one can assume that alterations in the antioxidant system may exacerbate the toxic effects generated by LPS endotoxin  It is also important to mention that Nrf2 levels drop as a consequence of the aging process(Godbout). This could lead one to propose that Nrf2 alterations from aging and other impairments and LPS may at least in part, mediate the effects in MCS. There has been evidence that hyperglycemia (which can be reversed with thyrotropin) sensitizes TRPV1 receptors which is implicated in MCS (Pall) and diabetes complications and TRPV1 may have direct or indirect effect on the release of neurotransmitters. (Pabbidi) Neuropeptides releases from capsaicin-sensitive efferents provide a protective mechanism against LPS but also increase bronchoconstriction which can increase airway hyperresponse. (Elekes) From these results and other studies, I have suggested that insulin resistance and hyperglycemia from chemical exposures may contribute to some of the inflammatory responses in MCS.

Endotoxin or LPS has been implicated as a possible pathway to the development of chronic fatigue syndrome. Above we noted that LPS increases the expression of toll-like receptors 2 and 4. Toll receptors recognize certain components on bacteria and transduces bacterial invasion through this recognition and has important relevance in preventing infection (Light) and expressed on a variety of cells including dendritic cells, B cells, neutraphils and macrophages. Defects in TLR expression can lead to an increase in susceptibility to infection from a number of pathogens while aberrant signaling of TLR such as from LPS are implicated in causing sepsis or even inflammatory or autoimmune-type conditions. (Harding) Activation of TLRs can lead to initiation of the the inflammatory pathway NF-kappaB and LPS endotoxins are ligand of TL4. Interestingly, saturated fats (bad fat) can induce inflammatory markers through TLR4 and therefore, saturated fats can alter gene expression through TLR4 interaction. For instance, the main component of coconut oil, lauric acid, has been demonstrated to potentiate the inflammatory effects of LPS COX-2. (Lee)  The just published Light study on chronic fatigue syndrome shows an increase in TLR4 after exercise and Light suggests this is due to "lesser fitness" in CFS patients. Light goes on to further explain that Il-10 is upregulated in CFS patients after exercise and one of its roles is to inhibit the production of Tnf-a which is also consistent with recent reports of an anti-inflammatory profile in FM. This and other studies of CFS revealed symptom flares may be related to cytokine activity postexercise. Notably, Tnf-a was elevated in muscle and Light explains that fatigue and muscle pain in CFS might be from the enhanced activation of "fatigue" and "nociceptive" afferents supplying muscle. Other supporting evidence of muscle involvement included elevations of ASIC3 channels that are often increased by muscle and joint inflammation. The elevation of Il-10 in the Light study was correlated to those patients with prolonged fatigue and pain but who also had elevations in pro-inflammatory cytokines and evidence of overall enhanced immune response. LPS has been shown to have a close relationship with sensory nerves and TLR4 receptors have been found on sensory nerves. The interaction between LPS and TLR4 may enhance the complications of TRPV1 activation. (Clark) In addition, Suter demonstrated that TLR2 and TLR4 are necessary for nerve-induced microglia activation and pain sensitization. (Suter)The presence of nociceptors on trigeminal nerves that suggests they recognize bacterial products and contribute to pain during infection. (Ball)

Citations and Original Document