Bidirectional modulation of TNF-α transcription via α- and β-adrenoceptors in cultured astrocytes from rat spinal cord

Noradrenaline (NA) suppresses TNF-alpha production via beta-adrenoceptors (ARs) in brain astrocytes. However, the downstream pathways from beta-ARs, and the involvement of alpha-ARs, remains unknown. In this study, we investigated the AR-mediated regulation of TNF-alpha mRNA levels in cultured astrocytes from rat spinal cord. NA, the aragonist phenylephrine, and the beta-agonist isoproterenol decreased the TNF-alpha mRNA level, while the alpha(2)-agonist dexmedetomidine increased it. The isoproterenol-induced TNF-alpha mRNA decrease was accompanied by a decrease in ERK phosphorylation. An adenylyl cyclase activator and an ERK inhibitor mimicked these effects. These results indicate that the transcriptional regulation of TNF-alpha by beta-ARs is mediated via cAMP pathways followed by the ERK pathway inhibition. The dexmedetomidine-induced TNF-alpha mRNA increase was accompanied by phosphorylation of JNK and ERK, which was blocked by a JNK inhibitor. Furthermore, the LPS-induced increase in the TNF-alpha mRNA level was accompanied by NF-kappa B nuclear translocation, and both these effects were blocked by phenylephrine. An NF-kappa B inhibitor suppressed the LPS-induced increase in the TNF-alpha mRNA level. These results suggest that alpha(1)-ARs suppress the LPS-induced increase in the TNF-alpha mRNA level via inhibition of NF-kappa B nuclear translocation. Taken together, our study reveals that both alpha- and beta-ARs are involved in the transcriptional regulation of TNF-alpha in astrocytes. (C) 2020 Elsevier Inc. All rights reserved.