Increasing the level of a naturally produced protein, called tristetraprolin (TTP), significantly reduced or protected mice from inflammation, according to NIEHS researchers. 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 journal Proceedings of the National Academy of Sciences.
Testing the role of the TTP gene
Inflammation plays 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 this growing health burden.
With that goal in mind, Perry Blackshear, M.D., D.Phil., head of the NIEHS Post-Transcriptional Gene Expression Group, led a team that genetically altered the TTP gene in mice, so that the animals produced higher than normal amounts of the protein. The mice were then tested using experimental models of rheumatoid arthritis, psoriasis, and multiple sclerosis. Experimental models are used to study processes believed 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."
Uncovering the mechanism
Blackshear said TTP exerts its beneficial effect by targeting several messenger molecules that encode cytokines, which are proteins known to be involved in inflammation. TTP binds to these molecules and destabilizes them, which results in lower levels of cytokines, thus leading to decreased inflammation.
Blackshear notes that ideally, TTP-based treatments would be cost effective and easy to administer. Future studies by Blackshear’s team will seek to identify compounds with 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."
Citation: Patial S, Curtis AD 2nd, 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 16;113(7):1865–1870.