Anti-inflammatory and anti-oxidant mechanisms of an MMP-8 inhibitor in lipoteichoic acid-stimulated rat primary astrocytes: involvement of NF-B, Nrf2, and PPAR- signaling pathways
- 주제(키워드) MMP-8 inhibitor , Astrocytes , Neuroinflammation , Anti-inflammatory , Antioxidant , Molecular mechanisms
- 주제(기타) Immunology; Neurosciences
- 설명문(일반) [Lee, Eun-Jung; Park, Jin-Sun; Lee, Yu-Young; Kim, Do-Yeon; Kim, Hee-Sun] Ewha Womans Univ, Tissue Injury Def Res Ctr, Sch Med, Dept Mol Med, Mok 6 Dong 911-1, Seoul 158710, South Korea; [Kang, Jihee Lee] Ewha Womans Univ, Sch Med, Dept Physiol, Tissue Injury Def Res Ctr, Seoul, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 BMC
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000155888
- 본문언어 영어
- Published As http://dx.doi.org/10.1186/s12974-018-1363-6
초록/요약
BackgroundRecent evidence suggests that reactive astrocytes play an important role in neuroinflammation and neurodegenerative diseases. Thus, controlling astrocyte reactivity has been suggested as a promising strategy for treating neurodegenerative diseases. In the present study, we investigated whether a matrix metalloproteinase (MMP)-8 inhibitor, M8I, could control neuroinflammation in lipoteichoic acid (LTA)-stimulated rat primary astrocytes.MethodsThe effects of M8I on the expression of inducible nitric oxide synthase, cytokines, and MMPs were examined in LTA-stimulated rat primary astrocytes by ELISA, RT-PCR, and Western blot analysis. The effects of M8I on reactive oxygen species (ROS) generation and phase II antioxidant enzyme expression were examined by the DCF-DA assay, RT-PCR, and Western blot analysis. The detailed molecular mechanisms underlying the anti-inflammatory and antioxidant effects of M8I were analyzed by the electrophoretic mobility shift assay, the reporter gene assay, Western blot, and RT-PCR analysis.ResultsTreatment with LTA, a major cell wall component of Gram-positive bacteria, led to astrocyte activation and induced the expression of inflammatory molecules such as iNOS, COX-2, and pro-inflammatory cytokines. In addition, LTA induced the expression of MMPs such as MMP-1, MMP-3, MMP-8, MMP-9, and MMP-13 in rat primary astrocytes. Based on previous reports showing that MMP-8 plays a role as a proinflammatory mediator in microglia, we investigated whether MMP-8 is also involved in inflammatory reactions of reactive astrocytes. We found that treatment of astrocytes with M8I significantly inhibited LTA-induced expression of iNOS, TNF-, IL-1, IL-6, and TLR-2. In addition, M8I inhibited LTA-induced NF-B, MAP kinase, and Akt activities, while it increased the anti-inflammatory PPAR- activities. Moreover, M8I showed antioxidant effects by suppressing ROS production in LTA- or H2O2-stimulated astrocytes. Interestingly, M8I increased the expression of phase II antioxidant enzymes such as hemeoxygenase-1, NQO1, catalase, and MnSOD by modulating the Nrf2/ARE signaling pathway.ConclusionsThe data collectively suggest the therapeutic potential of an MMP-8 inhibitor in neuroinflammatory disorders that are associated with astrocyte reactivity.
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