Figure 7

IL-1β activates astrocyte MAPK pathways, activates transcription factors and thereby regulates multiple human inflammation genes. IL-1β-mediated activation of astrocyte MAPK [p38K and ERK1/2] pathways precedes robust changes in gene expression. Multiple transcription factors traffic to astrocyte nuclei where they facilitate changes in mRNA transcription. Blocking IL-1β-mediated activation of astrocyte p38K blocks C/EBPβ translocation to nuclei [8]. The subsequent effects are similar to C/EBPβ knockdown; IL-1β-induced astrocyte TIMP-1 and COX-2 expression is blocked, and BDKRB2 expression is enhanced (Figure 4) [8]. ERK1/2 inhibition completely blocks IL-1β-induced astrocyte BDKRB2 expression and TIMP-1 expression, but enhances IL-1β-induced C/EBPβ and COX-2 expression (Figures 4 5 and 6) [8]. Two scenarios involving C/EBPβ could explain these events: (1) Blocking ERK1/2 signaling inhibits factors essential for IL-1β-induced astrocyte TIMP-1 expression and results in increased C/EBPβ translocation to nuclei to compensate for reduced TIMP-1 transcription. Increased C/EBPβ may account for increased COX-2. (2) Alternatively, ERK1/2 signaling may directly down-modulate IL-1β-induced astrocyte C/EBPβ; therefore, ERK1/2-selective inhibitors may increase COX-2 through an increase in CEBPβ activity. In either scenario, ERK1/2 is essential, and C/EBPβ is an auxiliary path to IL-1β-induced astrocyte TIMP-1. These data suggest MAPK, p38K and ERK1/2 are part of an intricate regulation network in which the two kinases balance one another’s activity to achieve a graded astrocyte response to CNS injury.