title: Protein kinase C δ (PKCδ)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade regulates glycogen synthase kinase-3 (GSK-3) inhibition-mediated interleukin-10 (IL-10) expression in lipopolysaccharide (LPS)-induced endotoxemia.
abstract: Glycogen synthase kinase-3 (GSK-3) modulates a wide array of cellular processes, including embryonic development, cell differentiation, survival, and apoptosis. Recently, it was reported that a GSK-3 inhibitor attenuates lipopolysaccharide (LPS)-induced septic shock and regulates the mortality of endotoxemic mice. However, the detailed mechanism of reduced mortality via GSK-3 inhibition is not well defined. Herein, we showed that GSK-3 inhibition induces extracellular signal-regulated kinase 1/2 (ERK1/2) activation under LPS-stressed conditions via protein kinase C δ (PKCδ) activation. Furthermore, PKCδ-induced ERK1/2 activation by the inhibition of GSK-3 provoked the production of interleukin (IL)-10, playing a crucial role in regulating endotoxemia. Using a mitogen-activated protein kinase kinase-1 (MEK-1) and PKCδ inhibitor, we confirmed that GSK-3 inhibition induces PKCδ and subsequent ERK1/2 activation, resulting in increased IL-10 expression under LPS-treated conditions. We verified that septic shock caused by LPS is attenuated by GSK-3 inhibition using a GSK-3 inhibitor. This relieved endotoxemia induced by GSK-3 inhibition was restored in an ERK1/2-dependent manner. Taken together, IL-10 expression produced by GSK-3 inhibition-induced ERK1/2 activation via PKCδ relieved LPS-mediated endotoxemia. This finding suggests that IL-10 hyperexpression resulting from GSK-3 inhibition-induced ERK activation could be a new therapeutic pathway for endotoxemia.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, South Korea.
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Noh
authors.forename: Kwang Hee
authors.initials: KH
authors.lastname: Son
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.forename: Hyun Kyu
authors.initials: HK
authors.lastname: Kang
authors.forename: Sun Ae
authors.initials: SA
authors.lastname: Hwang
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Ji Chang
authors.initials: JC
authors.lastname: You
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D003713:Dendritic Cells / Q000166:cytology; D019446:Endotoxemia / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007107:Immune System; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: D008070:Lipopolysaccharides; D016753:Interleukin-10; D009195:Peroxidase; D051745:Protein Kinase C-delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3