title: Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-α activation.
abstract: Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic plasticity, although aberrant expression of MMPs leads to brain damage, including blood-brain barrier disruption, inflammation, demyelination, and neuronal cell death. In this article, we report that MMP-8 is upregulated in LPS-stimulated BV2 microglial cells and primary cultured microglia, and treatment of MMP-8 inhibitor (M8I) or MMP-8 short hairpin RNA suppresses proinflammatory molecules, particularly TNF-α secretion. Subsequent experiments showed that MMP-8 exhibits TNF-α-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. Biochemical analysis of the underlying anti-inflammatory mechanisms of M8I revealed that it inhibits MAPK phosphorylation, NF-κB/AP-1 activity, and reactive oxygen species production. Further support for the proinflammatory role of microglial MMP-8 was obtained from an in vivo animal model of neuroinflammatory disorder. MMP-8 is upregulated in septic conditions, particularly in microglia. Administration of M8I or MMP-8 short hairpin RNA significantly inhibits microglial activation and expression/secretion of TNF-α in brain tissue, serum, and cerebrospinal fluid of LPS-induced septic mice. These results demonstrate that MMP-8 critically mediates microglial activation by modulating TNF-α activity, which may explain neuroinflammation in septic mouse brain.
authors: Department of Molecular Medicine and Global Top 5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea;
authors: Eun-Jung
authors: EJ
authors: Lee
authors: College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea;
authors: Jeong Eun
authors: JE
authors: Han
authors: Department of Molecular Medicine and Global Top 5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea;
authors: Moon-Sook
authors: MS
authors: Woo
authors: Department of Pharmacology, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea;
authors: Jin A
authors: JA
authors: Shin
authors: Department of Pharmacology, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea;
authors: Eun-Mi
authors: EM
authors: Park
authors: Department of Physiology, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea;
authors: Jihee Lee
authors: JL
authors: Kang
authors: Department of Molecular Medicine, Kyongbuk National University, Daegu 700-842, Republic of Korea; and.
authors: Pyong Gon
authors: PG
authors: Moon
authors: Department of Molecular Medicine, Kyongbuk National University, Daegu 700-842, Republic of Korea; and.
authors: Moon-Chang
authors: MC
authors: Baek
authors: College of Pharmacy, CHA University, Pocheon-si 487-010, Republic of Korea.
authors: Woo-Sung
authors: WS
authors: Son
authors: College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea;
authors: Young Tag
authors: YT
authors: Ko
authors: College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea; hskimp@ewha.ac.kr pharmchoi@gachon.ac.kr.
authors: Ji Woong
authors: JW
authors: Choi
authors: Department of Molecular Medicine and Global Top 5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea; hskimp@ewha.ac.kr pharmchoi@gachon.ac.kr.
authors: Hee-Sun
authors: HS
authors: Kim
mesh_terms: D051722:ADAM Proteins / Q000276:immunology; D000072198:ADAM17 Protein; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000276:immunology*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse