Metformin Down-regulates TNF-α Secretion via Suppression of Scavenger Receptors in Macrophages

Abstract

Obesity is consistently increasing in prevalence and can trigger insulin resistance and type 2 diabetes. Many lines of evidence have shown that macrophages play a major role in inflammation associated with obesity. This study was conducted to determine metformin, a widely prescribed drug for type 2 diabetes, would regulate inflammation through down-regulation of scavenger receptors in macrophages from obesity-induced type 2 diabetes. RAW 264.7 cells and peritoneal macrophages were stimulated with LPS to induce inflammation, and C57BL/6N mice were fed a high-fat diet to generate obesity-induced type 2 diabetes mice. Metformin reduced the production of NO, PGE2 and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) through down-regulation of NF-κB translocation in macrophages in a dose-dependent manner. On the other hand, the protein expressions of anti-inflammatory cytokines, IL-4 and IL-10, were enhanced or maintained by metformin. Also, metformin suppressed secretion of TNF-α and reduced the protein and mRNA expression of TNF-α in obese mice as well as in macrophages. The expression of scavenger receptors, CD36 and SR-A, were attenuated by metformin in macrophages and obese mice. These results suggest that metformin may attenuate inflammatory responses by suppressing the production of TNF-α and the expressions of scavenger receptors.

Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1 induction

“…The cell source of IL-4 is T cell, which might react differently to metformin from MNCs where IL-6 and TNF-a are derived from mcarophage. 24,25 Several randomized clinical studies have confirmed the benefits of metformin treatment, 6,8 including cardiovascular protection, lipid control, nonalcoholic simple fatty liver alleviation, and tumor inhibition. (E and F) The protein level of p65, acetyl-p65, and SIRT1 in MNCs of baseline (0 wk) after treatment for 12 weeks (12 wk).…”

Metformin prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction

“…Metformin reduced expression of pro-inflammatory and profibrotic genes in a mouse model of non-alcoholic hepatic steatosis (Kita et al, 2012), and reduced inflammation in the airways of asthmatic mice (Park et al, 2012). The anti-inflammatory effect of metformin could be due to inhibition of the NF-κB pathway, as evidenced in cultured cancer cells (Hirsch et al, 2013), vascular cells (Isoda et al, 2006), monocytes (Arai et al, 2010) and macrophages (Hyun et al, 2013). The anti-fibrotic effect of metformin has been characterized mostly in the cardiovascular system.…”

In vitro and in vivo anti-inflammatory activity of Phyllanthus acidus methanolic extract

“…Recent trials of anti-inflammatory drugs and remedies have concentrated on blocking the production of inflammatory gene products by suppressing the transcriptional activation of inflammatory genes (Ayele et al, 2013;Kim et al, 2013). For instance, targeting the signalling cascade that activates nuclear factor (NF)-κB and activator protein (AP)-1 has been shown to effectively inhibit the release of NO, PGE 2 , TNF-α, interleukin (IL)-1, MCP-1, and certain hydrolytic enzymes (Eo et al, 2013;Hyun et al, 2013). Much research has focused on identifying candidate materials that are safe and that can prevent inflammation-based diseases by inhibiting upstream signalling events involved in inflammatory gene expression.…”