TAK1 negatively regulates NF-κB and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils.
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.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Adebusola Alagbala
AA
Ajibade
Qinfu
Q
Wang
Jun
J
Cui
Jia
J
Zou
Xiaojun
X
Xia
Mingjun
M
Wang
Yanzheng
Y
Tong
Wei
W
Hui
Dou
D
Liu
Bing
B
Su
Helen Y
HY
Wang
Rong-Fu
RF
Wang
D000818:Animals; D017209:Apoptosis; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D015536:Down-Regulation; D017353:Gene Deletion; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D010641:Phenotype; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D039481:CD11b Antigen; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D019707:Receptors, Chemokine; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C503133:Gr-1 protein, mouse