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-I) 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-alpha (TGF-beta 1) increased PAI-I secretion in a dose- and time-dependent manner. PAI-1 protein increased by 3.2-fold and PAI-I mRNA by 1.9-fold after a 6-hour exposure to 400 pmol/L TGF-beta 1. This effect is probably mediated by TGF-beta 1 type 2 and 3 receptors, which were found to be expressed in cultured human adipocytes. Moreover, TNF-alpha and interkeukin-1 beta (IL-1 beta) 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-beta 1 mRNA is expressed by differentiation of human preadipocytes and is moderately upregulated by TNF-alpha and IL-beta, In conclusion, our results clearly indicate that TGF-beta is a potent inducer of PAI-1 production in subcutaneous human adipocytes. In addition, data suggest that TNF-alpha and IL-1 beta also have stimulatory effects on PAI-1 protein secretion and may contribute to the elevated PAI-1 levels observed in obesity.