Tumor necrosis factor a induces a metalloprotease-disintegrin, ADAM8 (CD 156): Implications for neuron-glia interactions during neurodegeneration

ADAM proteases, defined by extracellular disintegrin and metalloprotease do mains, are involved in protein processing and cell-cell interactions. Using wobbler (WR) mutant mice, we investigated the role of ADAMs in neurodegene ration and reactive glia activation in the CNS. We found that ADAM8 (CD 156 ), a suspected leukocyte adhesion molecule, is expressed in the CNS and hig hly 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 neuro degeneration occurs, ADAM8 is induced in neurons, reactive astrocytes, and activated microglia. Similarly, the proinflammatory cytokine tumor necrosis factor alpha (TN-alpha) is upregulated and shows the same cellular distrib ution. In primary astrocytes from wild-type and WR mice, in primary cerebel lar 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 b oth cell types, ADAM8 was also induced by human TNF-alpha, indicating that TNF receptor type I (p55) is involved. Induction of ADAM8 mRNA was suppress ed by treatment with an interferon-regulating factor 1 (IRF-1) antisense ol igonucleotide. We conclude that IRF-1-mediated induction of ADAM8 by TNF-al pha is a signaling pathway relevant for neurodegenerative disorders with gl ia activation, proposing a role for ADAM8 in cell adhesion during neurodege neration.