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Natural protein points to new inflammation treatment
 
 
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"TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases."
 
Thursday, February 4, 2016
 
Findings may offer insight to effective treatments for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
 
http://www.nih.gov/news-events/news-releases/natural-protein-points-new-inflammation-treatment
 
Increasing the level of a naturally-produced protein, called tristetraprolin (TTP), significantly reduced or protected mice from inflammation, according to researchers at the National Institutes of Health. The results suggest that pharmaceutical compounds or other therapeutic methods that produce elevated levels of TTP in humans may offer an effective treatment for some inflammatory diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis. The report appeared online Feb. 1 in the Proceedings of the National Academy of Sciences.
 
Inflammation has been proven to play a major role in a number of normal processes in humans, but it also fosters diseases, many of which are increasing in prevalence and severity. The development of new therapies for treating inflammatory diseases could greatly reduce the growing health burden.
 
With this goal in mind, Perry Blackshear, M.D., D.Phil., a researcher at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, led the team that genetically altered the TTP gene in mice, so that the animals produced higher than normal amounts of the TTP protein. The mice were then tested using experimental models of rheumatoid arthritis, psoriasis, and multiple sclerosis. Experimental models are used to study processes thought to be involved in human diseases, and to evaluate and select therapies that affect these processes.
 
"Mice with more TTP in their bodies were resistant to the inflammation that accompanied these experimental models of disease," Blackshear said. "We also found evidence of how TTP is providing this protection."
 
Blackshear said TTP exerts its beneficial effect by targeting several messenger molecules that encode cytokines, proteins known to be involved in inflammation. TTP binds to these molecules and destabilizes them, resulting in lower levels of cytokines and, thus, decreased inflammation.
 
Blackshear anticipates that TTP-based treatments would be cost effective and easy to administer. Future work will seek to identify compounds that have similar effects on the levels of TTP in the body.
 
"Many current therapies for these inflammatory diseases are expensive and require the medicines be introduced into the body under the skin, in the muscle, or by intravenous injection," said Sonika Patial, D.V.M., Ph.D., a research fellow in Blackshear's research group and lead author on the paper. "Our ideal treatments would be administered orally in pill or liquid form."
 
Reference
 
Patial S, Curtis II AD, Lai WS, Stumpo DJ, Hill GD, Flake GP, Mannie MD, Blackshear PJ. 2016. Enhanced stability of tristetrapolin mRNA protects mice against immune-mediated inflammatory pathologies. Proc Natl Acad Sci U S A; doi:10.1073/pnas.1519906113 [Online 1 February 2016].
 
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Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies
 
Significance

 
Inflammation is involved in the pathogenesis of many chronic diseases. Many deleterious effects of inflammation are mediated through increased production of proinflammatory mediators, known as cytokines and chemokines. Many current therapies for these diseases involve blocking single proinflammatory mediators, such as TNF, using parenteral administration of recombinant binding proteins. We demonstrate here that a genetic modification in the mouse that increases the expression of an endogenous antiinflammatory protein, tristetraprolin (TTP), results in protection against mouse models for several human inflammatory diseases, including rheumatoid arthritis, psoriasis, and multiple sclerosis, presumably by decreasing the production of proinflammatory cytokines. Our results suggest that increasing TTP expression may be an effective therapeutic strategy in the treatment of certain inflammatory diseases.
 
Abstract
 
Tristetraprolin (TTP) is an inducible, tandem zinc-finger mRNA binding protein that binds to adenylate-uridylate-rich elements (AREs) in the 3'-untranslated regions (3'UTRs) of specific mRNAs, such as that encoding TNF, and increases their rates of deadenylation and turnover. Stabilization of Tnf mRNA and other cytokine transcripts in TTP-deficient mice results in the development of a profound, chronic inflammatory syndrome characterized by polyarticular arthritis, dermatitis, myeloid hyperplasia, and autoimmunity. To address the hypothesis that increasing endogenous levels of TTP in an intact animal might be beneficial in the treatment of inflammatory diseases, we generated a mouse model (TTPΔARE) in which a 136-base instability motif in the 3'UTR of TTP mRNA was deleted in the endogenous genetic locus. These mice appeared normal, but cultured fibroblasts and macrophages derived from them exhibited increased stability of the otherwise highly labile TTP mRNA. This resulted in increased TTP protein expression in LPS-stimulated macrophages and increased levels of TTP protein in mouse tissues. TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases.
 
Taken together, our results support the hypothesis that moderately elevated levels of TTP throughout the body can have beneficial effects in some mouse models of immune and inflammatory disease. Current therapy of several human diseases of this type involves antibody- based molecules that bind directly to the relevant cytokine, such as anti-TNF compounds (33); these are produced by expensive recombinant DNA techniques and, because of their protein nature, require parenteral administration. Our data support the concept that therapies aimed at increasing levels or activities of TTP in cells throughout the body might benefit patients with these conditions. One possible approach to this is gene therapy; indeed, a previous study demonstrated protective effects of adenovirus-delivered TTP in an experimental periodontitis model (34). Other approaches might involve cell-based therapies, such as hematopoietic stem cell transplantation of genetically modified cells (35). Ideally, small molecules could be identified that, when administered orally, could cause elevations of TTP throughout the body. If such compounds could be identified that had minimal toxicity, it seems reasonable to suggest that they might be useful therapeutically in the treatment of certain chronic inflammatory diseases.

 
 
 
 
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