Role of cytokines in the regulation of plasminogen activator inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes.
Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are characteristic for obesity and are associated with increased risk of thromboembolic complications. PAI-1 recently was reported to be expressed and secreted by human adipocytes, but little is known about regulation of PAI-1 in human adipose tissue. Therefore, we examined the effects of selected cytokines present in adipose tissue on expression and secretion of PAI-1 in in vitro, differentiated subcutaneous human adipocytes in primary culture. Transforming growth factor-beta1 (TGF-beta1) increased PAI-1 secretion in a dose- and time-dependent manner. PAI-1 protein increased by 3.2-fold and PAI-1 mRNA by 1.9-fold after a 6-hour exposure to 400 pmol/L TGF-beta1. This effect is probably mediated by TGF-beta1 type 2 and 3 receptors, which were found to be expressed in cultured human adipocytes. Moreover, TNF-alpha and interkeukin-1beta (IL-1beta) also exerted a stimulatory effect on PAI-1 release and increased PAI-1 mRNA levels. As assessed by a semiquantitative reverse transcription-polymerase chain reaction technique, TGF-beta1 mRNA is expressed by differentiation of human preadipocytes and is moderately upregulated by TNF-alpha and IL-1beta. In conclusion, our results clearly indicate that TGF-beta1 is a potent inducer of PAI-1 production in subcutaneous human adipocytes. In addition, data suggest that TNF-alpha and IL-1beta also have stimulatory effects on PAI-1 protein secretion and may contribute to the elevated PAI-1 levels observed in obesity.
Birgel
M
M
Diabetes Research Institute at the Heinrich-Heine-University, Düsseldorf, Germany.
Gottschling-Zeller
H
H
Röhrig
K
K
Hauner
H
H
D017667:Adipocytes / Q000378:metabolism*; D002454:Cell Differentiation; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016207:Cytokines; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha