title: Promotion of autophagy at the maturation step by IL-6 is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity.
abstract: Increased autophagic vacuoles (AVs) occur in injured or degenerating neurons, under both developmental and pathological situations. Although an induced autophagy has been shown in inflammation response to cell factors, the underlying mechanism(s) remain(s) unknown. Here, we show that both cell factor IL-6 and environmental toxin MPP(+) promote the formation of vacuolation in SHSY5Y cells. By electron and immunofluorescent microscopy analyses, we showed that these structures are acid autolysosomes, containing cellular debris, and labeled by LC3 or LAMP1, markers of autophagosomes or lysosomes, respectively. Combining MPP(+) and IL-6 do not further increase vacuolation of SHSY5Y cells, and the vacuolation is less than that in the MPP(+)-treated group. MPP(+)-induced vacuolation results from significant increase in autophagy formation and delay in autophagy degradation, in relation to a decline of the lysosomal activity of arylsulfatase A. At molecular level, we show that this defect in autolysosomal maturation is independent of mammalian target of rapamycin and p38 inhibitions. Most importantly, we provide the first evidence that activation of ERK pathway is sufficient to commit cell to autophagic vacuolation. The sustained activation is required for MPP(+) to disrupt the autophagic pathway. IL-6 also induces a temporary and significant activation of ERK, but not sustained activation, and change sustained activation in MPP(+)-treated group into temporary activation. Taken together, these findings strongly support that IL-6 promotes the maturation of autophagosomes into functional autolysosomes by regulating ERK.
authors.affiliation: Department of Neurology, Jiangsu University Affiliated People's Hospital, No.8, Dianli Road, Zhenjiang 212002, Jiangsu, China. xuezhonglicn@yeah.net
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Li
authors.forename: Chen-Yan
authors.initials: CY
authors.lastname: Sui
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Xiong-Peng
authors.initials: XP
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhou
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002553:Cerebroside-Sulfatase / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D005419:Flavonoids; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002553:Cerebroside-Sulfatase; D015655:1-Methyl-4-phenylpyridinium; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one