title: Dexmedetomidine inhibits tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide-stimulated astrocytes by suppression of c-Jun N-terminal kinases.
abstract: Astrocytes play an important role in immune regulation in the central nervous system (CNS). Dexmedetomidine (DEX) has been reported to exert anti-inflammatory effects on astrocytes stimulated by lipopolysaccharide (LPS) both in vitro and in vivo studies. However, the underlying molecular mechanisms remain poorly understood. This study was designed to evaluate the effects of DEX on tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) gene expressions in LPS-challenged astrocytes. Moreover, c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (MAPK) pathways in LPS-challenged astrocytes were also investigated. In the present study, astrocytes were stimulated with LPS in the absence and presence of various concentrations of DEX. With real-time PCR assay, we found that LPS significantly increased expressions of TNF-α and IL-6 in mRNA level; however, these effects could be attenuated by DEX. Furthermore, JNK pathway might be involved in LPS-induced astrocyte activation because JNK phosphorylation was significantly increased, and the inhibition of this pathway mediated by DEX as well as SP600125 (JNK inhibitor) decreased TNF-α and IL-6 expressions. Moreover, p38 MAPK was also activated by LPS; however, this pathway seemed to have not participated in DEX-mediated LPS-induced inflammation. These results, taken together, suggest that JNK rather than p38 MAPK signal pathway, provides the potential target for the therapeutic effects of DEX for neuronal inflammatory reactions.
authors.affiliation: Department of Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, China.
authors.forename: Xiaobao
authors.initials: X
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Wenyi
authors.initials: W
authors.lastname: Qian
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Yanning
authors.initials: Y
authors.lastname: Qian
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020927:Dexmedetomidine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000873:Anthracenes; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D020927:Dexmedetomidine; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases