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(Circulation. 2005;111:1938-1945.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Inflammatory Cytokines Interleukin-6 and Oncostatin M Induce Plasminogen Activator Inhibitor-1 in Human Adipose Tissue

G. Rega, MD; C. Kaun, CTA; T.W. Weiss, MD; S. Demyanets, MD; G. Zorn, MTA; S.P. Kastl; S. Steiner, MD; D. Seidinger, MTA; C.W. Kopp, MD; M. Frey, MD; R. Roehle, MD; G. Maurer, MD; K. Huber, MD; J. Wojta, PhD

From the Department of Internal Medicine II (G.R., C.K., T.W.W., S.D., G.Z., S.P.K., S.S., D.S., C.W.K., G.M., J.W.), Medical University Vienna, and the Ludwig Boltzmann Foundation for Cardiovascular Research; Department of Surgery (M.F.), Medical University Vienna; 2nd Department of Surgery (R.R.), Wilhelminenspital; and 3rd Medical Department for Cardiology and Emergency Medicine (K.H.), Wilhelminenspital, Vienna, Austria.

Correspondence to Johann Wojta, Department of Internal Medicine II, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail johann.wojta{at}meduniwien.ac.at

Received November 5, 2004; revision received December 10, 2004; accepted December 21, 2004.

Background— Adipose tissue is a prominent source of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of plasminogen activation. Increased PAI-1 expression acts as a cardiovascular risk factor, and plasma levels of PAI-1 strongly correlate with body mass index (BMI). Elevated serum levels of interleukin-6 (IL-6), an inflammatory cytokine and a member of the glycoprotein 130 (gp130) ligand family, are found in obese patients and might indicate low-grade systemic inflammation. Another gp130 ligand, oncostatin M (OSM), upregulates PAI-1 in cardiac myocytes, astrocytes, and endothelial cells. We used tissue explants and primary cultures of preadipocytes and adipocytes from human subcutaneous and visceral adipose tissue to investigate whether IL-6 and OSM affect PAI-1 expression in fat.

Methods and Results— Human subcutaneous and visceral adipose tissue responded to treatment with IL-6 and OSM with a significant increase in PAI-1 production. Human preadipocytes were isolated from subcutaneous and visceral adipose tissue. Adipocyte differentiation was induced by hormone supplementation. All cell types expressed receptors for IL-6 and OSM and produced up to 12-fold increased levels of PAI-1 protein and up to 9-fold increased levels of PAI-1 mRNA on stimulation with IL-6 and OSM. AG-490, a janus kinase/signal transducer and activator of transcription inhibitor, abolished the OSM-dependent PAI-1 induction almost completely.

Conclusions— We have for the first time established a link between the gp130 ligands, the proinflammatory mediators IL-6 and OSM, and the expression of PAI-1 in human adipose tissue. Thus, we speculate that IL-6 and OSM, by upregulating PAI-1 in adipose tissue, can contribute to the increased cardiovascular risk of obese patients.

Key Words: obesity • inflammation • cardiovascular diseases • plasminogen • fibrinolysis

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