The pathogenesis of
bilirubin encephalopathy seems to result from accumulation of unconjugated
bilirubin (UCB) within the brain. We have recently demonstrated that UCB causes astroglial release of proinflammatory
cytokines and
glutamate, as well as cell death. The
bile acid glycoursodeoxycholic acid (GUDCA) and the anti-inflammatory
cytokine interleukin (IL)-10 have been reported to modulate
inflammation and cell survival. In this study we investigated the effect of these therapeutic agents on the astroglial response to UCB. Only GUDCA prevented UCB-induced astroglial death. The secretion of
tumor necrosis factor-alpha (
TNF-alpha) and IL-1beta elicited by UCB in astrocytes was reduced in the presence of GUDCA and
IL-10, whereas the suppression of
IL-6 was only counteracted by GUDCA. Neither GUDCA nor
IL-10 modulated the accumulation of extracellular
glutamate. Additionally,
IL-10 markedly inhibited UCB-induced
nuclear factor-kappaB nuclear translocation and
cytokine mRNA expression, whereas GUDCA only prevented
TNF-alpha mRNA expression. Moreover, GUDCA inhibited
TNF-alpha- and IL-1beta-converting
enzymes, preventing the maturation of these
cytokines and their consequent release. Collectively, this study shows that
IL-10 action is restricted to UCB-induced release of
TNF-alpha and IL-1beta from the astrocytes, whereas GUDCA presents a more ubiquitous action on the astroglial reactivity to UCB. Hence, GUDCA may have potential benefits over an
IL-10 therapeutic approach in reducing UCB-induced astrocyte immunostimulation and death.