PMID- 18088351
OWN - NLM
STAT- MEDLINE
DCOM- 20080617
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 6
IP  - 3
DP  - 2008 Mar
TI  - Antithrombin inhibits lipopolysaccharide-induced tumor necrosis factor-alpha 
      production by monocytes in vitro through inhibition of Egr-1 expression.
PG  - 499-507
AB  - BACKGROUND: Antithrombin (AT) improves the outcome of septic patients with 
      intravascular coagulation. However, the mechanisms underlying the therapeutic 
      benefits of AT are not fully understood. Tumor necrosis factor-alpha (TNF-alpha) 
      plays a critical role in the development of organ failure and intravascular 
      coagulation in sepsis. AIM: This study aimed to elucidate a molecular mechanism 
      by which AT inhibits TNF-alpha production. METHODS: Human peripheral monocyte was 
      stimulated by lipopolysaccharide (LPS) and TNF-alpha concentration in media was 
      measured. Levels of phosphorylation of extracellular signal-regulated protein 
      kinases (ERK) 1/2 and early growth response factor-1 (Egr-1) were estimated by 
      western blotting or by electrophoretic mobility shift assay. RESULTS: 
      Antithrombin (3 U mL(-1)) inhibited TNF-alpha production by monocytes stimulated 
      with LPS. Conversely, chemically modified AT that lacks affinity for heparin did 
      not. AT inhibited the phosphorylation of ERK 1/2 and decreased the expression of 
      Egr-1 in LPS-stimulated monocytes. However, it did not affect the activation of 
      either nuclear factor-kappaB or activator protein-1. Pretreatment with KT5720, a 
      protein kinase A inhibitor, reversed the inhibitory effect of AT on the 
      LPS-induced phosphorylation of ERK1/2. Although 2 U mL(-1) AT slightly inhibited 
      TNF-alpha production by LPS-stimulated monocytes, it significantly inhibited 
      TNF-alpha production in the presence of a low concentration of beraprost, a 
      stable derivative of prostacyclin. CONCLUSIONS: These observations suggest that 
      AT might inhibit LPS-induced production of TNF-alpha by inhibiting the increase 
      in Egr-1 expression in monocytes via interaction with heparin-like substances 
      expressed on the cell surface.
FAU - Komura, H
AU  - Komura H
AD  - Department of Anaesthesiology, Nagoya City University Graduate School of Medical 
      Sciences, Nagoya, Japan.
FAU - Uchiba, M
AU  - Uchiba M
FAU - Mizuochi, Y
AU  - Mizuochi Y
FAU - Arai, M
AU  - Arai M
FAU - Harada, N
AU  - Harada N
FAU - Katsuya, H
AU  - Katsuya H
FAU - Okajima, K
AU  - Okajima K
LA  - eng
PT  - Journal Article
DEP - 20071211
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Antithrombins)
RN  - 0 (Carbazoles)
RN  - 0 (EGR1 protein, human)
RN  - 0 (Early Growth Response Protein 1)
RN  - 0 (Indoles)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - 0 (Pyrroles)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 35E3NJJ4O6 (beraprost)
RN  - 58HV29I28S (KT 5720)
RN  - 9005-49-6 (Heparin)
RN  - DCR9Z582X0 (Epoprostenol)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Antithrombins/*metabolism
MH  - Carbazoles/pharmacology
MH  - Cell Survival
MH  - Early Growth Response Protein 1/*antagonists & inhibitors/*biosynthesis
MH  - Epoprostenol/analogs & derivatives/pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Heparin/chemistry
MH  - Humans
MH  - Indoles/pharmacology
MH  - Lipopolysaccharides/*metabolism
MH  - Models, Biological
MH  - Monocytes/*metabolism
MH  - Phosphorylation
MH  - Platelet Aggregation Inhibitors/pharmacology
MH  - Pyrroles/pharmacology
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
EDAT- 2007/12/20 09:00
MHDA- 2008/06/18 09:00
CRDT- 2007/12/20 09:00
PHST- 2007/12/20 09:00 [pubmed]
PHST- 2008/06/18 09:00 [medline]
PHST- 2007/12/20 09:00 [entrez]
AID - S1538-7836(22)12813-8 [pii]
AID - 10.1111/j.1538-7836.2007.02869.x [doi]
PST - ppublish
SO  - J Thromb Haemost. 2008 Mar;6(3):499-507. doi: 10.1111/j.1538-7836.2007.02869.x. 
      Epub 2007 Dec 11.