TNFα CAN BOTH UP- AND DOWN-REGULATE THE INDUCIBLE ANTIOXIDANT SYSTEMS IN ASTROCYTES.

CORREA F, LJUNGGREN E AND SANDBERG M.

Barga - Italia

Conferencia; Gordon Research Conferences - Thiol-Based Redox Regulation & Signaling; 2010

Gordon Research Conferences

Neuropathological processes in the central nervous system (CNS) are commonly accompanied by an activation of microglia and astrocytes. Amongst the several pro-inflammatory cytokines produced by activated glial cells, TNFalpha has been associated with both neuroprotective and neurotoxic effects. It has also been shown has been shown to modulate gluthatione (GSH) synthesis and the expression of GSH biosynthetic enzymes in other organs. However, little is know about the effects of this TNFalpha on the GSH levels and its biosynthetic machinery on astrocytes. Our main goal is to understand the effects of TNFalpha on astrocytes expression of GSH and other type II enzymes as well as the Nrf2/Keap1 system. We exposed primary cultures of astrocytes (7 days-in-vitro) to different doses of TNFalpha and analyse the content of GSH as well as other members of the Nrf2/Keap1 system at 24 and 72h post-stimulation. We found that 24h exposure to TNFalpha increased the expression of GSH, Nrf2 and the modulatory subunit of the gamma-glutamylcysteine ligase (gamma-GCLm; the rate limiting enzyme in GSH biosynthesis) whereas the levels of Keap1 where downregulated. The inducibility of the Nrf2/Keap1 was maintained, since the co-treatment with tBHQ further increased the levels of GSH. However, 72h exposure to TNFalpha induced a reduction in of GSH levels and a downregulation of Nrf2 as well as the modulatory and catalytic subunits of gamma-GCL expression followed by an upregulation of Keap1 expression. In this case, the inducibility of this system was lost. The treatment with tBHQ was unable to restore the contents of GSH and the expression of Nrf2 and gamma-GCL. These results demonstrate that the seemingly contradictory effects of TNFalpha observed here may explain the different reports suggesting neuroprotective as well as neurotoxic roles of these cytokine on the central nervous system.