Insulin enhancement of cytokine-induced coagulation/inflammation-related gene transcription in hepatocytes.
Hyperinsulinemia is a known risk factor for cardiovascular events, but its molecular basis is not completely understood. In this study, we examined the effects of insulin alone, or insulin and proinflammatory cytokines, on the expression of inflammation/coagulation-related genes in hepatocytes. We found that, in the HepG2 human hepatocyte cell line, insulin stimulated the transcriptional activity of plasminogen activator inhibitor 1 (PAI-1), fibrinogen-gamma and C-reactive protein (CRP) genes in time- and dose-dependent manners. These effects were completely inhibited by MAP kinase inhibitor PD98059, but not by PI3 kinase inhibitor wortmannin. As previously reported, proinflammatory cytokines like interleukin 1beta and interleukin 6 showed stimulatory effects on the expression of these genes, and we now found that the combination of insulin and the cytokines showed more than additive effects in most cases. Interleukin 1beta and insulin also cooperatively increased the endogenous mRNA level of PAI-1. These results suggest that the coexistence of high insulin and cytokines may induce inflammation and hypercoagulation in a synergistic manner. This may partly explain why the accumulation of multiple risk factors, especially hyperinsulinemia caused by insulin resistance and enhanced production of proinflammatory cytokines, results in inflammation, thrombosis, and cardiovascular events in metabolic syndrome.
Okazaki
Mizuho
M
Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Oko-cho, Nankoku, Japan.
Iwasaki
Yasumasa
Y
Jing
He
H
Nishiyama
Mitsuru
M
Taguchi
Takafumi
T
Tsugita
Makoto
M
Taniguchi
Yoshinori
Y
Kambayashi
Machiko
M
Hashimoto
Kozo
K
D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics*; D016207:Cytokines / Q000494:pharmacology*; D004338:Drug Combinations; D005419:Flavonoids / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D018836:Inflammation Mediators / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D004338:Drug Combinations; D005419:Flavonoids; D018836:Inflammation Mediators; D007328:Insulin; D053583:Interleukin-1beta; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one