Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue.
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.


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.
Rega
G
G
Department of Internal Medicine II, Medical University Vienna, and the Ludwig Boltzmann Foundation for Cardiovascular Research, Vienna, Austria.
Kaun
C
C
Weiss
T W
TW
Demyanets
S
S
Zorn
G
G
Kastl
S P
SP
Steiner
S
S
Seidinger
D
D
Kopp
C W
CW
Frey
M
M
Roehle
R
R
Maurer
G
G
Huber
K
K
Wojta
J
J
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008024:Ligands; D008562:Membrane Glycoproteins; D008875:Middle Aged; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D018121:Receptors, Cytokine / Q000032:analysis; D019947:Receptors, Interleukin-6 / Q000032:analysis; D053677:Receptors, Oncostatin M; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D004791:Enzyme Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; C508351:OSM protein, human; D010455:Peptides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; D053677:Receptors, Oncostatin M; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053683:Oncostatin M; D050822:Cytokine Receptor gp130