TAK1 Negatively Regulates NF-κB and p38 MAP Kinase Activation in Gr-1 +CD11b + Neutrophils

Adebusola Alagbala Ajibade, Qinfu Wang, Jun Cui, Jia Zou, Xiaojun Xia, Mingjun Wang, Yanzheng Tong, Wei Hui, Dou Liu, Bing Su, Helen Yicheng Wang, Rongfu Wang

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)43-54
Number of pages12
JournalImmunity
Volume36
Issue number1
DOIs
StatePublished - Jan 27 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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