1: Circ Res. 2005 Aug 19;97(4):305-13. Epub 2005 Jul 21. 

Interleukin-10 suppresses tissue factor expression in
lipopolysaccharide-stimulated macrophages via inhibition of Egr-1 and a serum
response element/MEK-ERK1/2 pathway.

Kamimura M, Viedt C, Dalpke A, Rosenfeld ME, Mackman N, Cohen DM, Blessing E,
Preusch M, Weber CM, Kreuzer J, Katus HA, Bea F.

Department Internal Medicine III, University of Heidelberg, Heidelberg, Germany.

Atherosclerosis is considered to be an inflammatory disease. Tissue factor (TF),
a prothrombotic molecule expressed by various cell types within atherosclerotic
plaques, is thought to play an essential role in thrombus formation after
atherosclerotic plaque rupture. Recent studies suggest that the antiinflammatory
cytokine interleukin-10 (IL-10) has many antiatherosclerotic properties.
Therefore, the effects of IL-10 on TF expression in response to inflammation
were investigated. Mouse macrophages were stimulated with lipopolysaccharide
(LPS) in the presence or absence of IL-10. Pretreatment with IL-10 resulted in a
50% decrease in TF mRNA expression and TF promoter activity. Binding of early
growth response gene-1 (Egr-1) to the consensus DNA sequence, a key
transcriptional activator of TF expression in response to inflammation, and the
expression of Egr-1 mRNA were also inhibited by IL-10. This inhibition was
independent of the induction of suppressor of cytokine signaling protein-3 by
IL-10. Macrophages that had been transfected with luciferase reporter constructs
containing the murine Egr-1 5'-flanking sequence exhibited reduced reporter gene
activity in response to LPS stimulation with IL-10 pretreatment. Studies with
deletion constructs of the Egr-1 promoter identified the proximal serum response
element SRE3 as a potential regulatory site for the IL-10 mediated suppression
of Egr-1 expression. Furthermore, activation of the upstream signal-transduction
elements, such as mitogen-activated protein kinase kinase (MEK) 1/2,
extracellular signal-regulated kinase 1/2, and Elk-1 were also inhibited by
IL-10 pretreatment. Taken together, these results demonstrate a pathway for the
IL-10 mediated inhibition of TF expression during inflammation and may explain
the antiatherosclerotic effects of IL-10.

PMID: 16037570 [PubMed - indexed for MEDLINE]


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