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 journalArticlepeer-review

10 Citations (Scopus)


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
Issue number2
Publication statusPublished - 2013 Feb

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)


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