Proteins in Bone Health, Development and Disease in Environmental Illness

Proteins in Bone Health, Development and Disease in Environmental Illness

CRH and Tregs in Autoimmunity: Possible Connections to Chemical Sensitivity~!

Background: In earlier posts we described how commensal bacteria in the gut regulates the induction of T regulatory cells called Tregs that are important for immune functions. The loss of which may include autoimmune-type expressions and may be influential in MCS by loss of tolerance. In addition, we have also discussed how cortico-releasing hormone (CRH or CRF) has many effects and tissue targets, can be influenced by odors, may influence addictive-type behaviors and abherrant signaling may lead to altered signaling that can lead to mood disorders and have other negative influences on behaviors. The activation of CRH is part of the stress response and therefore, become an important part of the response to environmental cues. This same response activates the inflammatory cascade and therefore, the existence of one may coincide with the activation of the other. In addition, inflammatory cascades include activation of immune cells including mast cells.

Christy and Brown explain that Tregs are important in autoimmune disease and have the potential upon induction to prevent and reverse these conditions including diabetes and multiple sclerosis. Both of which are now considered to have an environmental connection. In addition the author notes that lupus, another condition with possible environmental triggers, and other autoimmune conditions are not just a loss of Tregs but a condition where other immune cells called Ag-effector cells become resistent to Treg suppression. At this point, one would suggest that other physiological pathways may be involved and this potentiates the non-adaptive conditions that lead to MCS. In other blogs, we have discussed a number of these conditions including nutrition and expression of cytokines, as well as, the expression of Nrf2.

Christy and Brown also present another important factor that very well may influence the development of MCS by contributing to loss of tolerance and that is the production of CRH from mast cells. These cells are often produced from inflammatory reactions such as those conditions that produced and reported from environmental toxin exposure. The authors discuss how the role of CRH produced from these inflammatory cells in basically an uptapped area of immune science. On the other hand, Soderholm does note that mast cells and CRH are implicated in disruptions of barrier function in irritable bowel syndrome and to a degree, it it now understood they are produced in inflamed tissue and increase inflammation. This protein has been implicated in reactions in rheumatoid arthritis and other inflammatory conditions during stress. For this reason, one can suggest that inflammatory conditions and production of mast cells which can produce this protein may contribute to the response and long-term activation can have important effects on downstream targets and participate in autoimmune-type response such as those observed in chemical sensitivities.

Past HEIRS Blogs: Related Tags: CRF , CRH , Nrf2


Christy, A. L. and Brown, M. A. (2007). The multitasking mast cell: Positive and negative roles in the progression of autoimmunity. J Immunol, 179(5):2673-2679.
http://www.citeulike.org/user/HEIRS/article/7357936
McKay, D. M. (2005). Good bug, bad bug: in the case of enteric inflammatory disease does the epithelium decide? Memórias do Instituto Oswaldo Cruz, 100(s1):205-210.

http://www.citeulike.org/user/HEIRS/article/7357955
Teitelbaum, A. A., Gareau, M. G., Jury, J., Yang, P. C., and Perdue, M. H. (2008). Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress. Am J Physiol Gastrointest Liver Physiol, 295(3):G452-459. http://www.citeulike.org/user/HEIRS/article/7357961

Connections: Hearing Loss and Inflammatory Bowel Disease

CiteULike: Sensorineural Hearing Loss in Pediatric Patients with Inflammatory Bowel Disease: "Sensorineural Hearing Loss in Pediatric Patients with Inflammatory Bowel Disease"

Regulation of Interleukin-10 Gene Expression in Macrophages Engulfing Apoptotic Cells

Summary: Production of IL-10 by phagocytes during clearance of ACs is critical to ensuring cellular homeostasis and suppression of autoimmunity.

CiteULike: Regulation of Interleukin-10 Gene Expression in Macrophages Engulfing Apoptotic Cells: "Zhang, Y., Kim, H.-J., Yamamoto, S., Kang, X., and Ma, X. (2010). Regulation of interleukin-10 gene expression in macrophages engulfing apoptotic cells. Interferon and Cytokine Research."

GSK-3b and the Inflammatory Response in Environmental Illnesses

Some experts believe that Il-6 is an important cytokine in the activation of autoimmune and inflammatory diseases, some forms of cancer and present at high levels in PTSD. GSK-3b has been our recent topic of discussion and some important considerations for the actions of this protein is its overexpression may contribute to a number of mental and physical health conditions. Its activities provide a sort-of "on-off" switch for the antioxidant system Nrf2 and inhibits the expression of PGC-1 and for this reason is an important regulator of cellular homeostasis and energy metabolism. It has also been demonstrated GSK-3b inhibits heat shock factor which has important implications for studies of lifespan. Heat shock factor assists in the control of stress response activation through heat shock proteins which have protective properties that "aid in folding, transport, regulation, and degradation of cellular proteins under normal conditions, and their expression during stress is essential for cell survival." (Xavier) Heat shock factor has the ability to "repress" the expression of Il-1 through a transcription mechanism associated with Il-6 and thereby, limiting inflammatory responses. (Xie) These studies suggest that overexpression of GSK-3b (ie. that may occur from endotoxin-induced production of Tnf-a) may contribute to activation of immune responses that are "autoimmune or inflammatory" in nature. It also provides more evidence of the role of Nrf2 in autoimmune-type responses and that inhibition of PGC-1a may contribute to dysregulation of metabolism associated with environmental illness.

Notes:

• SIRT1 regulates the expression of HSF which can be elevated by resveratrol.

Xavier et al. Glycogen Synthase Kinase 3B Negatively Regulates Both DNA-Binding and Transcriptional Activities of Heat Shock Factor 1. June 2000. http://www.citeulike.org/user/HEIRS/article/6590895
Ishihara, K. and Hirano, T. (2002). Il-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine & growth factor reviews, 13(4-5):357-368. http://www.citeulike.org/user/HEIRS/article/4365589
Maes, M. (1999). Elevated serum interleukin-6 (il-6) and il-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biological Psychiatry, 45(7):833-839. http://www.citeulike.org/user/HEIRS/article/4509997
Xie, Y., Chen, C., Stevenson, M. A., Auron, P. E., and Calderwood, S. K. (2002). Heat shock factor 1 represses transcription of theil-1β gene through physical interaction with the nuclear factor of interleukin 6. Journal of Biological Chemistry, 277(14):11802-11810. http://www.citeulike.org/user/HEIRS/article/6590793
Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N. K., Yan, Z., and Spiegelman, B. M. (2007). Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in pgc-1  alpha muscle-specific knock-out animals. The Journal of biological chemistry, 282(41):30014-30021. http://www.citeulike.org/user/HEIRS/article/1907765
Corton, J. C. and Brown-Borg, H. M. (2005). Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci, 60(12):1494-1509. http://www.citeulike.org/user/HEIRS/article/2339648

Etiological and biological aspects (ie AhR,Th-17) of cigarette smoking in rheumatoid arthritis.

One would suspect that pollutants are a major factor considering involvement with the AhR and this author makes some interesting points that RA started in the New World in the N American population and spread to Europe suggesting a vector-born disease.....??
TENNESSEE ORIGINS OF RHEUMATOID ARTHRITIS  by Bruce M. Rothschild

Etiological and biological aspects of cigarette smoking in rheumatoid arthritis.: "Onozaki, K. (2009). Etiological and biological aspects of cigarette smoking in rheumatoid arthritis. Inflammation & allergy drug targets, 8(5):364-368"

Genetic dissection of systemic autoimmune disease in nrf2 deficient mice.

Title: Genetic dissection of systemic autoimmune disease in nrf2 deficient mice.

Summary: "SLE occurs with an prevalence as high as 1 in 2,500 people but predominantly affects women (35). SLE is especially prevalent in women during their childbearing years (9:1 female to male ratio) and during pregnancy, suggesting a role of female hormones in development of the disease. Most mouse models of SLE also exhibit an increased susceptibility of females to the disease. The sex-specific decreases in glutathione S-transferase -1 and -2 and µ-1, -2, and -3 have been shown previously in the livers of nrf2 knockout mice (10) and are in agreement with our study (Table 3). The findings from this data and other reports strongly suggest that a deficiency in detoxification and increased oxidative stress can result in the development of a systemic autoimmune disease."

Li, J., Stein, T. D., and Johnson, J. A. (2004). Genetic dissection of systemic autoimmune disease in nrf2 deficient mice. Physiological Genomics, pages 1-57.  http://www.citeulike.org/user/HEIRS/article/6012655

Estrogen May Make Women Prone To Autoimmune-type Il-1b Inflammatory Conditions

Title: Alternatively activated macrophages in infection and autoimmunity.

Summary: "Women may be at an increased risk of M2-mediated infection and autoimmunity due to estrogen's ability to increase Th2 responses."

Citation: Fairweather, D. and Cihakova, D. (2009). Alternatively activated macrophages in infection and autoimmunity. Journal of autoimmunity. http://www.citeulike.org/user/HEIRS/article/5948117

Distribution of inducible nitric oxide synthase and tumor necrosis factor- in the peripheral nervous system of lewis rats during ascending paresis and spontaneous recovery from experimental autoimmune neuritis

Autoimmune Neuritis: Peripheral nerve inflammation caused by injury, poisoning, or disease, and accompanied by sensory and motor changes in the area of the affected nerve.

Title: Distribution of inducible nitric oxide synthase and tumor necrosis factor- in the peripheral nervous system of lewis rats during ascending paresis and spontaneous recovery from experimental autoimmune neuritis.

Summary: "is the first report to show iNOS- and TNF--immunoreactive cells in dorsal root ganglia during EAN, suggesting an underlying pathology for the neuropathic pain behavior in EAN. Our results suggest that the cells bearing iNOS and TNF- in the different parts of the peripheral nervous system are involved in the development of the clinical signs observed at each stage of EAN."

De La Hoza, C. L. R., Castrob, F. R., Santosc, L. M. B., and Langonec, F. (2010). Distribution of inducible nitric oxide synthase and tumor necrosis factor- in the peripheral nervous system of lewis rats during ascending paresis and spontaneous recovery from experimental autoimmune neuritis. Neuroimmunomodulation, 17(1). http://www.citeulike.org/user/HEIRS/article/5891598