title: LYATK1 potently inhibits LPS-mediated pro-inflammatory response.
abstract: Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings.
authors.affiliation: Department of Intensive Care Unit, Taixing People(')s Hospital, Taixing, Jiangsu Province, 225400, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xi
authors.affiliation: Department of Ophthalmology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Intensive Care Unit, Taixing People(')s Hospital, Taixing, Jiangsu Province, 225400, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Intensive Care Unit, Taixing People(')s Hospital, Taixing, Jiangsu Province, 225400, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.affiliation: Department of Intensive Care Unit, Taixing People(')s Hospital, Taixing, Jiangsu Province, 225400, China. Electronic address: taixingzhaofeng163@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000818:Animals; D016207:Cytokines / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D000067996:RAW 264.7 Cells; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D000099151:MAP Kinase Kinase Kinase 7
keywords: LPS; LYTAK1; Monocytes/macrophages and inflammation; TAK1 signalings