title: Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock.
abstract: Lipopolysaccharide (LPS), one of the most prominent pathogen-associated molecular patterns (PAMPs), activates macrophages, causing release of toxic cytokines (i.e. tumor necrosis factor (TNF)-α) that may provoke inflammation and endotoxin shock. Here, we tested the potential role of trametinib, a novel and highly potent MAPK/ERK kinase (MEK) inhibitor, against LPS-induced TNF-α response in monocytes, and analyzed the underlying mechanisms. We showed that trametinib, at nM concentrations, dramatically inhibited LPS-induced TNF-α mRNA expression and protein secretion in transformed (RAW 264.7 cells) and primary murine macrophages. In ex-vivo cultured human peripheral blood mononuclear cells (PBMCs), this MEK inhibitor similarly suppressed TNF-α production by LPS. For the mechanism study, we found that trametinib blocked LPS-induced MEK-ERK activation in above monocytes, which accounted for the defective TNF-α response. Macrophages or PBMCs treated with a traditional MEK inhibitor PD98059 or infected with MEK1/2-shRNA lentivirus exhibited a similar defect as trametinib, and nullified the activity of trametinib. On the other hand, introducing a constitutively-active (CA) ERK1 restored TNF-α production by LPS in the presence of trametinib. In vivo, mice administrated with trametinib produced low levels of TNF-α after LPS stimulation, and these mice were protected from LPS-induced endotoxin shock. Together, these results show that trametinib inhibits LPS-induced TNF-α expression and endotoxin shock probably through blocking MEK-ERK signaling.
authors: Department of Emergency, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors: Du
authors: D
authors: Shi-Lin
authors: Department of Emergency, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors: Xue
authors: X
authors: Yuan
authors: Department of Emergency, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors: Sun
authors: S
authors: Zhan
authors: Department of Emergency, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors: Tang
authors: T
authors: Luo-Jia
authors: Department of Emergency, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, China. Electronic address: tcyangfudan1976@126.com.
authors: Tong
authors: T
authors: Chao-Yang
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D055815:Young Adult
chemical_list: D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D014409:Tumor Necrosis Factor-alpha; C560077:trametinib; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Lipopolysaccharide (LPS); MEK-ERK signaling and endotoxin shock; Trametinib; Tumor necrosis factor (TNF)-α