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Houston Methodist. Leading Medicine

Research Brief: A Kinase called TAK1 Controls Inflammation in the Body with Tailored Effects in Diff

A Kinase called TAK1 Controls Inflammation in the Body by Tailoring Its Effects to Different Cell Types

HOUSTON (January 27, 2012) - A new paper in Immunity by TMHRI Center for Inflammation and Epigenetics Director Rongfu Wang, Ph.D., and others identifies an entirely unexpected role for TAK1 (TGF-beta activated kinase 1). The protein kinase that plays a critical role in activating B- and T-cells during an immune response appears to have the opposite effect on myeloid cells, suppressing the development of neutrophils. It is the first time that the kinase has been shown to exert opposite effects on a signaling cascade depending on cell type.

"When you delete this gene, mice develop a lot of inflammation and produce large amounts of proinflammatory cytokines, which can lead to a wide range of health issues," says Wang, who led the research. "TAK1 could link inflammation to many diseases such as cancer, obesity and autoimmunity."

Wang was joined in the research by Adebusola Alagbala Ajibade, Qinfu Wang, Jun Cui, Jia Zou, Xiaojun Xia, Mingjun Wang, Yanzheng Tong, Wei Hui, and Helen Y. Wang of The Methodist Hospital Research Institute, and Dou Liu and Bing Su of the Yale University School of Medicine. Rongu Wang and Helen Wang both had coappointments at the Baylor College of Medicine when the research was conducted. This work is in part supported by grants from National Cancer Institute, NIH (R01 and P01) and Cancer Research Institute.

Based on a series of deletion experiments, Wang and his coauthors report that TAK1 activates MAP kinases p38 and I?B kinase (IKK) in B- and T-cells, but reduced the activity of p38 and IKK in neutrophils. TAK1 ablation, Wang says, led to increased phosphorylation of p38 and IKK as well as production of reactive oxygen species (ROS) (see an illustration or cartoon below).

"In the past, scientists focused on B- and T- cells, but didn't pay too much attention to neutrophils," Wang says. "Recent studies show critical roles of neutrophils in innate and adaptive immunity. When you have an infection or tissue damage, neutrophils are the first set of cells to come to the inflammatory sites. Given TAK1's importance to the immune response in B- and T-cells, we wanted to look at its impact in myeloid cells, in particular neutrophils, as well. So our findings are very striking and show the opposite effects on innate immune signaling and ROS production in neutrophils."

TAK1, (also known as Map3k7), is critical for the development of different immune cell types, Wang says. Scientists aren't just interested in learning how TAK1 and other kinases fit into the complex network of cell biology and immune response, but to learn whether key players in the pathways are adequate targets for therapy.

"Understanding how neutrophils behave and what genes drive them will help us understand the process of inflammation and the body's response to it," Wang says. "And understanding neutrophils, which are involved in responding to inflammation caused by infectious pathogens, cancer, and possibly even obesity, will help us understand these diseases better, too."

To speak with Dr. Wang or a representative of TMHRI, please contact David Bricker, The Methodist Hospital, at 832-667-5811 or dmbricker@houstonmethodist.org.  For more information on The Methodist Hospital Research Institute, visit our website. Follow Methodist on Facebook and Twitter.