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

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8 引文 斯高帕斯(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.
頁(從 - 到)207-217
期刊Journal of Molecular Medicine
出版狀態已發佈 - 2月 2013

ASJC Scopus subject areas

  • 分子醫學
  • 藥物發現
  • 遺傳學(臨床)


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