Thrombin induces the expression of oncostatin M via AP-1 activation in human macrophages: a link between coagulation and inflammation.
Macrophages as inflammatory cells are involved in the pathogenesis of atherosclerosis that today is recognized as an inflammatory disease. Activation of coagulation leads to the late complication of atherosclerosis, namely atherothrombosis with its clinical manifestations stroke, unstable angina, myocardial infarction, and sudden cardiac death. Thus inflammation and coagulation play fundamental roles in the pathogenesis of atherosclerosis. We show that the coagulation enzyme thrombin up-regulates oncostatin M (OSM), a pleiotropic cytokine implicated in the pathophysiology of vascular disease, in human monocyte-derived macrophages (MDMs) up to 16.8-fold. A similar effect was seen in human peripheral blood monocytes and human plaque macrophages. In MDMs, the effect of thrombin on OSM was abolished by PPACK and mimicked by a PAR-1-specific peptide. Thrombin induced phosphorylation of ERK1/2 and p38 in MDMs. The ERK1/2 inhibitor PD98059 blocked the effect of thrombin on OSM production in MDMs, whereas the p38 inhibitor SB202190 had no effect. Thrombin induced translocation of c-fos and c-jun to the nucleus of MDMs. Using OSM promoter-luciferase reporter constructs transfected into MDMs, we show that a functional AP-1 site is required for promoter activation by thrombin. We present another link between coagulation and inflammation, which could impact on the pathogenesis of atherosclerosis.
Kastl
Stefan P
SP
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
Speidl
Walter S
WS
Katsaros
Katharina M
KM
Kaun
Christoph
C
Rega
Gersina
G
Assadian
Afshin
A
Hagmueller
Georg W
GW
Hoeth
Martina
M
de Martin
Rainer
R
Ma
Yongsheng
Y
Maurer
Gerald
G
Huber
Kurt
K
Wojta
Johann
J
D001777:Blood Coagulation / Q000235:genetics*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D053683:Oncostatin M / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
D044463:Receptor, PAR-1; D018808:Transcription Factor AP-1; D053683:Oncostatin M; D048052:Mitogen-Activated Protein Kinase 3; D013917:Thrombin