Selective inhibition of tumor necrosis factor-α synthesis in murine microglia by a novel adenosine carbocyclic nucleoside analogue

HTV-1 actively infects microglia in the CNS and stimulates these cells to synthesize cytokines. These molecules, particularly TNFcc, IL-1 and IL-6 augment HTV-1 replication and have been linked to neurological symptoms in AIDS including anorexia A novel carbocyclic nucleoside analogue (MDL 201,112) that regulates peritoneal macrophages by inhibiting TNFa has been described (Parmely et al., J. Immunol. 151:389) The purpose of this study was to examine the effects of a similar adenosine anaologue, MDL201,449A (a gift from Marion Merrell Dow Research Institute, Marion Merrell Dow Inc ), on TNFa synthesis and secretion by microglial cells. A murine microglial cell line (N13) and primary microglia isolated from brain of 1-2 dold BALB/c mice were primed with murine WN-y (100 U/mL) and incubated in the presence of LPS (0, 10, 100 and 1000 ng/mL) and MDL201.449A (0, 10, 100 and 1000 uM). The adenosine analogue, MDL201.449A, inhibited TNFa, but not IL-6, production by activated primary microglia and the murine microglial cell line, N13. Northern blot analysis indicated that MDL201.449A inhibited the expression of TNFa mKNA in IFNy + LPS activated N13 cells, suggesting the carbocyclic nucleoside analogue inhibited TNFa synthesis rather than secretion. These data suggest that MDL201.449A and other adenosine analogues may be useful for inhibiting TNFa synthesis by microglia in the CNS.