title: AS-703026 Inhibits LPS-Induced TNFα Production through MEK/ERK Dependent and Independent Mechanisms.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by intense lung infiltrations of immune cells (macrophages and monocytes). Lipopolysaccharide (LPS) activates macrophages/monocytes, leading to production of tumor necrosis factor α (TNFα) and other cytokines, which cause subsequent lung damages. In the current study, our results demonstrated that AS-703026, a novel MEK/ERK inhibitor, suppressed LPS-induced TNFα mRNA expression and protein secretion in RAW 264.7 murine macrophages, and in murine bone marrow-derived macrophages (BMDMs). Meanwhile, TNFα production in LPS-stimulated COPD patents' peripheral blood mononuclear cells (PBMCs) was also repressed by AS-703026. At the molecular level, we showed that AS-703026 blocked LPS-induced MEK/ERK activation in above macrophages/monocytes. However, restoring ERK activation in AS-703026-treated RAW 264.7 cells by introducing a constitutive-actively (CA)-ERK1 only partially reinstated LPS-mediated TNFα production. Meanwhile, AS-703026 could still inhibit TNFα response in ERK1/2-depleted (by shRNA) RAW 264.7 cells. Significantly, we found that AS-703026 inhibited LPS-induced nuclear factor κB (NFκB) activation in above macrophages and COPD patients' PBMCs. In vivo, oral administration of AS-703026 inhibited LPS-induced TNFα production and endotoxin shock in BALB/c mice. Together, we show that AS-703026 in vitro inhibits LPS-induced TNFα production in macrophages/monocytes, and in vivo protects mice from LPS-induced endotoxin shock. Thus, it could be further studied as a useful anti-inflammatory therapy for COPD patients.
authors.affiliation: Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of clinical immunology and pathogenic examination, Xi'an Medical University, Xi'an, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide