TAK1 kinase is an indispensable intermediate in the intracellular signaling of innate immune responses. TAK1 is activated by many of distinct factors including Toll-like receptor ligands, intracellular microorganism sensor (NOD like receptor) ligands, IL-1 and TNF. TAK1 upregulates proinflammatory responses through activation of NF-B and mitogen activated protein kinase pathways. Thus, TAK1 is generally considered to be a positive regulator of inflammation. However, we have recently found that the targeted deletion of TAK1 in the epithelium of skin and intestine results in severe inflammation. These inflammatory conditions in the TAK1 mutant mice resemble chronic inflammatory diseases such as psoriasis in the skin and Crohn's disease in the intestine. We have found that TAK1 deletion causes accumulation of reactive oxygen species (ROS), and that inhibition of ROS can completely rescue cell death in cultured epithelial cells. Importantly, we found that treatment of the antioxidants in the epithelial-specific TAK1 deletion mice could prevent the epithelial cell death and diminishes inflammation. Therefore, we hypothesize that ablation of TAK1 signaling in epithelial cells causes dysregulation of ROS that is involved in epithelial cell death and inflammation. The objectives of this proposal are;1) to determine the mechanism by which ROS regulates epithelial cell death and inflammation;2) to identify the cause of ROS accumulation in TAK1-deficient epithelium. Outcomes from this project will delineate the relationship between ROS regulation and chronic inflammation, which could result in new approaches to regulate inflammation.

Public Health Relevance

Inflammatory diseases such as inflammatory bowel disease are major health problems; however their pathogeneses and effective treatments still remain identified. Epithelial inflammation can be caused by dysregulated activation of immune cells and also by loss of epithelial integrity. We have found that ablation of a kinase TAK1 in epithelial cells destroys epithelial integrity and induces inflammatory conditions in a mouse model. We have so far found that TAK1 regulates reactive oxygen species (ROS), which is important to prevent inflammation. In this project, we will delineate the pathway that dysfunctional TAK1- induced ROS causes inflammation. The results from this project will provide better understanding in molecular pathogenesis of epithelial-derived inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM084406-01A2
Application #
7731035
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dunsmore, Sarah
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$310,405
Indirect Cost
Name
North Carolina State University Raleigh
Department
Public Health & Prev Medicine
Type
Schools of Earth Sciences/Natur
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Omori, Emily; Inagaki, Maiko; Mishina, Yuji et al. (2012) Epithelial transforming growth factor ?-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species. Proc Natl Acad Sci U S A 109:3365-70
Morioka, Sho; Inagaki, Maiko; Komatsu, Yoshihiro et al. (2012) TAK1 kinase signaling regulates embryonic angiogenesis by modulating endothelial cell survival and migration. Blood 120:3846-57
Omori, E; Matsumoto, K; Ninomiya-Tsuji, J (2011) Non-canonical ?-catenin degradation mediates reactive oxygen species-induced epidermal cell death. Oncogene 30:3336-44
Broglie, Peter; Matsumoto, Kunihiro; Akira, Shizuo et al. (2010) Transforming growth factor beta-activated kinase 1 (TAK1) kinase adaptor, TAK1-binding protein 2, plays dual roles in TAK1 signaling by recruiting both an activator and an inhibitor of TAK1 kinase in tumor necrosis factor signaling pathway. J Biol Chem 285:2333-9
Kajino-Sakamoto, Rie; Omori, Emily; Nighot, Prashant K et al. (2010) TGF-beta-activated kinase 1 signaling maintains intestinal integrity by preventing accumulation of reactive oxygen species in the intestinal epithelium. J Immunol 185:4729-37
Omori, Emily; Matsumoto, Kunihiro; Zhu, Songyun et al. (2010) Ablation of TAK1 upregulates reactive oxygen species and selectively kills tumor cells. Cancer Res 70:8417-25
Kim, Jae-Young; Kajino-Sakamoto, Rie; Omori, Emily et al. (2009) Intestinal epithelial-derived TAK1 signaling is essential for cytoprotection against chemical-induced colitis. PLoS One 4:e4561