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Secretory phospholipase A 2 plays an essential role in microglial inflammatory responses to Mycobacterium tuberculosis
Author(s) -
Yang ChulSu,
Yuk JaeMin,
Shin DongMin,
Kang Junghee,
Lee Sung Joong,
Jo EunKyeong
Publication year - 2008
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20832
Subject(s) - biology , p38 mitogen activated protein kinases , microglia , microbiology and biotechnology , proinflammatory cytokine , signal transduction , phospholipase a2 , kinase , nitric oxide synthase , reactive oxygen species , tumor necrosis factor alpha , protein kinase c , mapk/erk pathway , phosphorylation , inflammation , phospholipase a , nitric oxide , immunology , biochemistry , enzyme , endocrinology
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)‐κB 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. © 2008 Wiley‐Liss, Inc.