ABSTRACT
ADAM proteases, defined by extracellular disintegrin and metalloprotease domains, are involved in protein processing and cell-cell interactions. Using wobbler (WR) mutant mice, we investigated the role of ADAMs in neurodegeneration and reactive glia activation in the CNS. We found that ADAM8 (CD 156), a suspected leukocyte adhesion molecule, is expressed in the CNS and highly induced in affected CNS areas of WR mice, in brainstem and spinal cord. ADAM8 mRNA and protein are found at low levels throughout the normal mouse CNS, in neurons and oligodendrocytes. In the WR CNS regions in which neurodegeneration occurs, ADAM8 is induced in neurons, reactive astrocytes, and activated microglia. Similarly, the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is upregulated and shows the same cellular distribution. In primary astrocytes from wild-type and WR mice, in primary cerebellar neurons, and in mouse motoneuron-like NSC19 cells, ADAM8 expression was induced up to 15-fold by mouse TNF-alpha, in a dose-dependent manner. In both cell types, ADAM8 was also induced by human TNF-alpha, indicating that TNF receptor type I (p55) is involved. Induction of ADAM8 mRNA was suppressed by treatment with an interferon-regulating factor 1 (IRF-1) antisense oligonucleotide. We conclude that IRF-1-mediated induction of ADAM8 by TNF-alpha is a signaling pathway relevant for neurodegenerative disorders with glia activation, proposing a role for ADAM8 in cell adhesion during neurodegeneration.
Subject(s)
Antigens, CD , Antigens, Surface/biosynthesis , Heredodegenerative Disorders, Nervous System/metabolism , Membrane Proteins/biosynthesis , Neuroglia/metabolism , Neurons/metabolism , Tumor Necrosis Factor-alpha/metabolism , ADAM Proteins , Animals , Antigens, Surface/analysis , Antigens, Surface/genetics , Cell Communication/drug effects , Cell Extracts/chemistry , Cell Line , Cell Survival/drug effects , Central Nervous System/metabolism , Central Nervous System/pathology , Cytokines/biosynthesis , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/genetics , Disintegrins/biosynthesis , Dose-Response Relationship, Drug , Gene Expression/drug effects , Heredodegenerative Disorders, Nervous System/genetics , Heredodegenerative Disorders, Nervous System/pathology , Interferon Regulatory Factor-1 , Membrane Proteins/analysis , Membrane Proteins/genetics , Metalloendopeptidases/biosynthesis , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Neuroglia/cytology , Neuroglia/pathology , Neurons/cytology , Neurons/pathology , Oligonucleotides, Antisense/pharmacology , Organ Specificity/genetics , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/genetics , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/biosynthesis , Transcriptional Activation , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Reactive astrocytes occurring in response to neurodegeneration are thought to play an important role in neuronal regeneration by upregulating the expression of extracellular matrix (ECM) components as well as the ECM degrading metalloproteinases (MMPs). We examined the mRNA levels and cellular distribution of membrane type matrix metalloproteinase 1 (MT1-MMP) and tissue inhibitors 1-4 of MMPs (TIMPs) in brain stem and spinal cord of wobbler (WR) mutant mice affected by progressive neurodegeneration and astrogliosis. MT1-MMP, TIMP-1 and TIMP-3 mRNA levels were elevated, whereas TIMP-2 and TIMP-4 expression was not affected. MT1-MMP was expressed in reactive astrocytes of WR. In primary astrocyte cultures, MT1-MMP mRNA was upregulated by exogeneous tumor necrosis factor alpha. Increased plasma membrane and secreted MMP activities were found in primary WR astrocytes.
