1. TAK1 Negatively Regulates NF-κB and p38 MAP Kinase Activation in Gr-1+CD11b+ Neutrophils
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Alagbala Ajibade, Adebusola, Wang, Qinfu, Cui, Jun, Zou, Jia, Xia, Xiaojun, Wang, Mingjun, Tong, Yanzheng, Hui, Wei, Liu, Dou, Su, Bing, Wang, Helen Y., and Wang, Rong-Fu
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MITOGEN-activated protein kinases , *NEUTROPHILS , *IMMUNE response , *T cells , *B cells , *NEUTROPHIL immunology - Abstract
Summary: Stringent control of NF-κB and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-β activated kinase-1 (TAK1) is essential for NF-κB activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7 ΔM/ΔM) led to development of splenomegaly and lymphomegaly associated with neutrophilia. Compared with wild-type cells, TAK1-deficient neutrophils enhanced the phosphorylation of the kinases IKK, p38, and JNK and the production of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7 ΔM/ΔM mice were significantly more susceptible to LPS-induced septic shock and produced higher amounts of IL-1β, IL-6, and TNF-α in plasma than do wild-type mice. Specific ablation of p38 rescued the phenotype and functional properties of Map3k7 ΔM/ΔM mice. Our findings identify a previously unrecognized role of TAK1 as a negative regulator of p38 and IKK activation in a cell type-specific manner. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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