Glycogen synthase kinase-3β inactivation is an intracellular marker and regulator for endotoxemic neutrophilia

Tsan-Tzu Yang, Chia-Ling Chen, Wei-Chieh Lin, Yee-Shin Lin, Po-Chun Tseng, Chia-Yuan Hsieh, Yu-Hong Chen, Wei-Ching Huang, Cheng-Chieh Tsai, Chi-Yun Wang, Chi-Chang Shieh, Chiou Feng Lin

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Neutrophilia, defined as a large number of neutrophils in the circulating blood, is caused by increased differentiation and survival from activation-induced apoptosis. Regulation of apoptosis is essential for neutrophil homeostasis; however, the molecular signaling that regulates this process needs further investigation. Unlike TLR4 wild-type C3H/HeN mice, TLR4 mutated C3H/HeJ mice were insusceptible to LPS-induced blood neutrophilia. LPS prevented constitutive apoptosis in neutrophils and partly involved a blockade of the mitochondrial pathway including mitochondria transmembrane potential loss, myeloid cell leukemia sequence (Mcl) 1 degradation, and caspase-3 activation. In apoptotic neutrophils, glycogen synthase kinase (GSK)-3β was activated, and inhibiting GSK-3β decreased Mcl-1 degradation and apoptosis. LPS caused p38 MAPK-, JNK-, and PI3K/AKT-mediated Mcl-1 stabilization and prevented apoptosis, and LPS induced GSK-3β inactivation mainly through p38 MAPK and PI3K/AKT. Neutrophils in the neutrophilia showed increased GSK-3β inactivation and Mcl-1 stabilization accompanied by activation of p38 MAPK, JNK, and AKT. Notably, LPS-induced ROS generation can partly facilitate p38 MAPK/JNK/AKT activation to regulate GSK-3β-mediated Mcl-1 stability, apoptosis, and neutrophilia. These results demonstrate that the molecular basis of endotoxemic neutrophilia is through a direct action on neutrophils involving GSK-3β inactivation to prevent constitutive apoptosis.

Original languageEnglish
Pages (from-to)207-217
Number of pages11
JournalJournal of Molecular Medicine
Volume91
Issue number2
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

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Keywords

  • AKT
  • Apoptosis
  • Glycogen synthase kinase-3β
  • LPS
  • Mcl-1
  • Neutrophil
  • Neutrophilia
  • p38 MAPK
  • ROS

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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