Metformin, an Antidiabetic Agent, Suppresses the Production of Tumor Necrosis Factor and Tissue Factor by Inhibiting Early Growth Response Factor-1 Expression in Human Monocytes in Vitro

Abstract

Metformin, an antidiabetic agent, has been shown to reduce atherothrombotic disease in diabetic patients independent of antihyperglycemic effect. Recent studies have demonstrated that metformin attenuates the proinflammatory responses in human vascular wall cells and macrophages. However, the detailed molecular mechanisms underlying these therapeutic effects remain unclear. In the present study, we investigated the effects of metformin on tumor necrosis factor (TNF) production and tissue factor (TF) expression in isolated human monocytes stimulated with lipopolysaccharide (LPS) or oxidized low-density lipoprotein (oxLDL). Metformin significantly inhibited both TNF production and TF expression in isolated human monocytes stimulated with LPS or oxLDL. Metformin also significantly inhibited TNF and TF mRNA in human monocytes stimulated with LPS. Although metformin did not inhibit the activation of either nuclear factor-B or activator protein-1, it inhibited the expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 in monocytes stimulated with LPS or oxLDL. These results suggest that metformin may attenuate the inflammatory responses, at least in part, by suppressing the production of both TNF and TF through the inhibition of the ERK1/2-Egr-1 pathway in human monocytes.

ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK

“…In our model using primary human MDMs, AMPK activation by ETC-1002 inhibits LPSinduced MAPK signaling as refl ected in the reduced phosphorylation of JNK and p38. Similar inhibition of JNK and p38 phosphorylation has been previously demonstrated for AMPK activators in macrophage cell lines as well as in human monocytes where pharmacological activation of AMPK offsets immune responses in a MAPK-dependent fashion ( 26,30 ).…”

“…In clinical studies, ETC-1002 has not only demonstrated improved lipid profi les but also revealed signifi cantly attenuated levels of hsCRP ( 19 ), an independent risk factor for CAD and a well-established clinical biomarker of infl ammation ( 20,21 ). Pharmacological activation of AMPK has been previously shown to limit infl ammatory response in vitro and in vivo (22)(23)(24)(25)(26), and several signaling pathways, including Akt, GSK, SIRT, and NFkB, have been associated with anti-infl ammatory consequences of AMPK activation ( 17,(27)(28)(29). While the exact mechanism of AMPK-dependent regulation of the immune response remains unclear, inhibition of mitogen-activated protein kinases (MAPK), such as JNK and p38, has been recently linked to AMPK-dependent anti-infl ammatory signaling ( 30 ).…”

The role of tissue factor in normal pregnancy and in the development of preeclampsia: A review

“…estrogen, in cigarette smokers and in hyperhomocysteinemia [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] .…”

Repurposing Metformin for Lung Cancer Management

“…Like tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-kB) and signal transducer and activator of transcription 3 (STAT3) are important components of the inflammation reaction. Arai et al elucidated that metformin reduces the process and production of TNF-α in human monocytes [17].…”