Thrombomodulin expression by THP-1 but not by vascular endothelial cells is upregulated by pioglitazone.
Thrombomodulin-protein C pathway is a major anti-thrombotic mechanism present in endothelial cells (EC), and an important modulator of inflammation. Peroxisomal proliferator activated receptor-gamma (PPARgamma) expressed in monocytes/macrophages may have a role in cell differentiation. Since the expression of thrombomodulin (TM) by monocytes is upregulated during differentiation into macrophages, we investigated the effect of pioglitazone, a thiazolidinedione (TZD) that is a synthetic ligand of PPARgamma, on the expression of TM by a human monocyte/macrophage cell line; human acute monocytic leukemia (THP-1) cells. Pioglitazone dose-dependently upregulated TM antigen expression by THP-1 cells accompanied by an upregulation of TM cofactor activity for thrombin-dependent protein C activation. Thrombomodulin mRNA expression in THP-1 cells was also upregulated by pioglitazone, whereas tissue factor (TF) mRNA expression was not induced at all. Treatment cells with a natural PPARgamma ligand, 15-deoxy-delta12,14-prostaglandin J(2) (PGJ2), also enhanced TM protein expression. PGF(2alpha) an agent known to inactivate PPARgamma, diminished the stimulatory effect of pioglitazone and PGJ2 on TM protein expression. In contrast, pioglitazone had no effect on TM antigen expression by human umbilical vein ECs. These results suggest that PPARgamma activation in macrophages may counteract potentially prothrombotic and putative inflammatory properties in activated macrophages.
Kanehara
Hideo
H
Third Department of Internal Medicine, Faculty of Medicine, Fukui Medical University, Japan.
Tohda
Gen
G
Oida
Koji
K
Suzuki
Jinya
J
Ishii
Hidemi
H
Miyamori
Isamu
I
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015152:Blotting, Northern; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D018180:Thrombomodulin / Q000235:genetics* / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D018180:Thrombomodulin; D014157:Transcription Factors; C037112:9-deoxy-delta-9-prostaglandin D2; D013925:Thromboplastin; D015230:Prostaglandin D2; D000077205:Pioglitazone