Plasminogen activator inhibitor-1 expression and secretion are stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes.
Various adipocytokines have been described which influence insulin sensitivity and vascular function profoundly and might, therefore, potentially link obesity, insulin resistance, and atherosclerosis. Among those, plasminogen activator inhibitor (PAI)-1 is an adipose-secreted factor upregulated in obesity and insulin resistance that inhibits fibrinolysis. Furthermore, recent studies in knockout mice suggest that PAI-1 directly impairs insulin sensitivity. In the current study, the impact of growth hormone (GH) and interleukin (IL)-6 on PAI-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6. Other insulin resistance-inducing hormones which stimulated PAI-1 synthesis included insulin, TNFalpha, and dexamethasone. Studies using pharmacological inhibitors suggested that basal and GH-induced PAI-1 synthesis were at least in part mediated by p44/42 mitogen-activated protein kinase but not janus kinase 2 and phosphatidylinositol 3-kinase. Taken together, our results show a differential regulation of PAI-1 mRNA by insulin resistance-inducing hormones including GH and IL-6.
Kralisch
Susan
S
University of Leipzig, Department of Internal Medicine III, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany.
Klein
Johannes
J
Lossner
Ulrike
U
Blüher
Matthias
M
Paschke
Ralf
R
Stumvoll
Michael
M
Fasshauer
Mathias
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D013997:Time Factors
D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D013006:Growth Hormone; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1