PMID- 26381508
OWN - NLM
STAT- MEDLINE
DCOM- 20160526
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 9
DP  - 2015
TI  - AS-703026 Inhibits LPS-Induced TNFalpha Production through MEK/ERK Dependent and 
      Independent Mechanisms.
PG  - e0137107
LID - 10.1371/journal.pone.0137107 [doi]
LID - e0137107
AB  - 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 alpha (TNFalpha) 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 TNFalpha mRNA expression and protein secretion in 
      RAW 264.7 murine macrophages, and in murine bone marrow-derived macrophages 
      (BMDMs). Meanwhile, TNFalpha 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 TNFalpha production. Meanwhile, AS-703026 could still inhibit 
      TNFalpha response in ERK1/2-depleted (by shRNA) RAW 264.7 cells. Significantly, we 
      found that AS-703026 inhibited LPS-induced nuclear factor kappaB (NFkappaB) activation in 
      above macrophages and COPD patients' PBMCs. In vivo, oral administration of 
      AS-703026 inhibited LPS-induced TNFalpha production and endotoxin shock in BALB/c 
      mice. Together, we show that AS-703026 in vitro inhibits LPS-induced TNFalpha 
      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.
FAU - Li, Ping
AU  - Li P
AD  - Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong 
      University, Xi'an, China.
FAU - Wu, Yonghong
AU  - Wu Y
AD  - Department of clinical immunology and pathogenic examination, Xi'an Medical 
      University, Xi'an, China.
FAU - Li, Manxiang
AU  - Li M
AD  - The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
FAU - Qiu, Xiaojuan
AU  - Qiu X
AD  - Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong 
      University, Xi'an, China.
FAU - Bai, Xiaoyan
AU  - Bai X
AD  - Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong 
      University, Xi'an, China.
FAU - Zhao, Xiaojing
AU  - Zhao X
AD  - Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong 
      University, Xi'an, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150918
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Lipopolysaccharides)
RN  - 0 (N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 25X51I8RD4 (Niacinamide)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/*drug effects/metabolism
MH  - Cell Line
MH  - Lipopolysaccharides/*pharmacology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Macrophages/*drug effects/metabolism
MH  - Mice
MH  - Niacinamide/*analogs & derivatives/pharmacology
MH  - Signal Transduction/*drug effects
MH  - Tumor Necrosis Factor-alpha/*metabolism
PMC - PMC4575053
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/09/19 06:00
MHDA- 2016/05/27 06:00
PMCR- 2015/09/18
CRDT- 2015/09/19 06:00
PHST- 2015/07/01 00:00 [received]
PHST- 2015/08/12 00:00 [accepted]
PHST- 2015/09/19 06:00 [entrez]
PHST- 2015/09/19 06:00 [pubmed]
PHST- 2016/05/27 06:00 [medline]
PHST- 2015/09/18 00:00 [pmc-release]
AID - PONE-D-15-27572 [pii]
AID - 10.1371/journal.pone.0137107 [doi]
PST - epublish
SO  - PLoS One. 2015 Sep 18;10(9):e0137107. doi: 10.1371/journal.pone.0137107. 
      eCollection 2015.