title: Secretory phospholipase A2 plays an essential role in microglial inflammatory responses to Mycobacterium tuberculosis.
abstract: In previous studies, we have shown that reactive oxygen species (ROS)-mediated inflammatory signaling is essential for microglial proinflammatory responses to Mycobacterium tuberculosis (Mtb). To further investigate the molecular mechanisms governing these processes, we sought to describe the role of phospholipase A(2) (PLA(2)) in Mtb-induced ROS generation and inflammatory mediator release by microglia. Inhibition of secretory PLA(2) (sPLA(2)), but not cytosolic PLA(2) (cPLA(2)), profoundly abrogated Mtb-mediated ROS release, the generation of various inflammatory mediators (tumor necrosis factor, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinase-2 and -9), and the activation of nuclear factor (NF)-kappaB and MAPKs (ERK1/2, p38, and JNK/SAPK) by murine microglial BV-2 cells or primary mixed glial cells. Interruption of the Ras/Raf-1/MEK1/ERK1/2 pathway abolished Mtb-induced sPLA(2) activity, whereas the blockage of JNK/SAPK or p38 activity had no effect. Specific inhibition of sPLA(2), but not cPLA(2), suppressed the upregulation of ERK1/2 phosphorylation by Mtb stimulation, suggesting the existence of a mutual dependency between the ERK1/2 and sPLA(2) pathways. Moreover, examination of the protein kinase C (PKC) family revealed that classical PKCs are involved in Mtb-induced sPLA(2) activation by microglia. Taken together, our results demonstrate for the first time that sPLA(2), either through pathways comprising Ras/Raf-1/MEK1/ERK1/2 or the classical PKC family, plays an essential role in Mtb-mediated ROS generation and inflammatory mediator release by microglial cells.
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Yuk
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Junghee
authors.initials: J
authors.lastname: Kang
authors.forename: Sung Joong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D018920:Coculture Techniques; D004660:Encephalitis / Q000201:enzymology* / Q000382:microbiology / Q000503:physiopathology; D005911:Gliosis / Q000201:enzymology* / Q000382:microbiology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D054497:Phospholipases A2, Secretory / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016862:Tuberculoma, Intracranial / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D014390:Tuberculosis, Meningeal / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D054497:Phospholipases A2, Secretory; D018631:ras Proteins