TNF-ALPHA INHIBITS SCHWANN-CELL PROLIFERATION, CONNEXIN46 EXPRESSION,AND GAP JUNCTIONAL COMMUNICATION

Schwann cell responses to nerve injury are stimulated, in part, by inf lammatory cytokines. This study compares changes in the phenotype of c ultured Schwann cells after exposure to the cytokine tumor necrosis fa ctor (TNF)-alpha or the mitogen neu differentiation factor (NDF)-beta. TNF alpha inhibited proliferation in a dose-dependent manner without altering Schwann cell survival. TNF alpha also reduced both gap juncti onal conductance and Lucifer yellow dye coupling between Schwann cells , Moreover, both P-0 and glial fibrillary acidic protein (GFAP) immuno reactivity were reduced, By contrast, NDF beta initially had little ef fect on cell division although it reduced junctional coupling within 8 h. However, by 48 h, NDF beta stimulated proliferation with a concomi tant increase in coupling. Dividing Schwann cells (BrdU(+)) were prefe rentially dye coupled compared to nondividing cells, indicating an ass ociation between proliferation and coupling, Moreover, cultured Schwan n cells expressed connexin46 mRNA and protein, and changes in the leve ls of the protein correlated with the degree of proliferation and coup ling. The data thus provide evidence for cytokine-induced modulation o f Schwann cell antigenic phenotype, proliferation, and gap junction pr operties. These observations suggest that enhanced gap junctional comm unication among Schwann cells after nerve injury could help to coordin ate cellular responses to the injury, and that TNF alpha may be a sign al which terminates proliferation as well as junctional communication.