Adiponectin Specifically Increased Tissue Inhibitor of Metalloproteinase-1 Through Interleukin-10 Expression in Human Macrophages

Abstract

Background-Vascular inflammation and subsequent matrix degradation play an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipose-specific plasma protein, accumulated to the injured artery and attenuated vascular inflammatory response. Clinically, high plasma adiponectin level was associated with low cardiovascular event rate in patients with chronic renal failure. The present study was designed to elucidate the effects of adiponectin on matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in human monocyte-derived macrophages. Methods and Results-Human monocyte-derived macrophages were incubated with the physiological concentrations of human recombinant adiponectin for the time indicated. Adiponectin treatment dose-dependently increased TIMP-1 mRNA levels without affecting MMP-9 mRNA levels. Adiponectin also augmented TIMP-1 secretion into the media, whereas MMP-9 secretion and activity were unchanged. Time course experiments indicated that TIMP-1 mRNA levels started to increase at 24 hours of adiponectin treatment and were significantly elevated at 48 hours. Adiponectin significantly increased interleukin-10 (IL-10) mRNA expression at the transcriptional level within 6 hours and significantly increased IL-10 protein secretion within 24 hours. Cotreatment of adiponectin with anti-IL-10 monoclonal antibody completely abolished adiponectin-induced TIMP-1 mRNA expression. Conclusions-Adiponectin selectively increased TIMP-1 expression in human monocyte-derived macrophages through IL-10 induction. This study identified, for the first time, the adiponectin/IL-10 interaction against vascular inflammation. Key Words: proteins Ⅲ glycoproteins Ⅲ metalloproteinases Ⅲ interleukins Ⅲ inflammation C urrent advances in basic science have illustrated the role of inflammation and its mechanisms, which contribute to atherosclerotic diseases. Inflammatory processes are not only associated with initiation and progression of atherosclerosis but are also responsible for acute thrombotic complications. Most coronary artery thrombi are triggered by the rupture of atherosclerotic plaque lesions, which are controlled by the balance between matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitor of metalloproteinases [TIMPs]), mainly secreted from activated macrophages. 1 However, the precise mechanisms have not been elucidated fully. Adipose tissue secretes various bioactive molecules, termed adipocytokines, that directly contribute to obesity-linked metabolic and vascular diseases. Adiponectin is an adipocytespecific plasma protein that we identified in a human adipose tissue cDNA library. 2 We have reported that physiological concentrations of human recombinant adiponectin suppressed tumor necrosis factor-␣ (TNF-␣)-induced endothelial adhesion molecule expression, transformation from macrophage to foam cell, and TNF-␣ expression in macrophages. 3,4 Clinical hypoadiponectinemia was observed in patients with obesity, type 2 diabetes mellit...

Obesity and thyroid cancer

“…It is produced exclusively by adipocytes; pro-inflammatory factors such as TNFa, IL6, and ROS can exert a regulatory effect on adiponectin expression (Li et al 2009). This adipokine is able to improve insulin sensitivity, influence cell proliferation, and regulate the balance of anti-and pro-inflammatory molecules and cells, such as TNFa, IL10, macrophages, T-cells, and NK-cells, always aiming to control inflammation (Yokota et al 2000, Kumada et al 2004, Takemura et al 2007. In order to develop these functions, adiponectin binds to two different receptors: AdipoR1 and AdipoR2.…”

Matrix metalloproteinase-9 genetic variations affect MMP-9 levels in obese children

“…19 Interestingly, we found lower TIMP-1 concentrations and lower adiponectinemia in obese children compared with non-obese children, and these findings are consistent with the idea that adiponectin (an adipose-specific protein and anti-atherogenic factor) modulates TIMP-1 expression by macrophages. 26 Although several polymorphisms have been detected in the MMP-9 gene, the C-1562T polymorphism increases MMP-9 expression as a result of loss of a nuclear repressor protein binding site when the T allele is present. 8 The lower MMP-9 levels that we found in obese subjects not carrying the T allele is supported by this previous finding.…”

The role of fat topology in the risk of disease

“…Adiponectin increases the expression of mRNA and protein production of TIMP in macrophages. 37 Before the induction of TIMP formation and secretion, adiponectin has been shown to induce IL-10 synthesis in macrophages, suggesting that adiponectin induces TIMP formation and secretion through the induction of IL-10 synthesis in an autocrine manner in macrophages, thus possibly inhibiting matrix metalloproteinase activity. 34 These functions may result in the prevention of acute coronary syndrome.…”