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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:871.)
© 2008 American Heart Association, Inc.

Integrated Physiology/Experimental Medicine

Effects of Statins on Adipose Tissue Inflammation

Their Inhibitory Effect on MyD88-Independent IRF3/IFN-β Pathway in Macrophages

Manabu Abe; Morihiro Matsuda; Hironori Kobayashi; Yugo Miyata; Yuki Nakayama; Ryutaro Komuro; Atsunori Fukuhara; Iichiro Shimomura

From the Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan. Current affiliation for M.A.: Biological Research Laboratories II, Daiichi-Sankyo Co Ltd, Hiromachi, Shinagawa-ku, Tokyo, Japan.

Correspondence to Morihiro Matsuda, MD, PhD, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan. E-mail mmatsuda{at}imed2.med.osaka-u.ac.jp

Objectives— Macrophage-mediated chronic inflammation of adipose tissue is causally linked to insulin resistance in obesity. The beneficial effects of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) on glucose metabolism have been suggested, but the effects of these agents on adipose tissue inflammation are unclear. The aim of the present study is to define the effects of statins on adipose tissue inflammation and macrophages.

Methods and Results— Pravastatin or pitavastatin treatment of obese mice attenuated an increase in mRNA expressions of proinflammatory genes, including MCP1 and IL6, in adipose tissue. The supernatant of TLR4-stimulated RAW264 macrophages strongly induced the expression of these genes in 3T3-L1 adipocytes, which was inhibited by pretreatment of macrophages with either statin. Statins inhibited TLR4-mediated activation of interferon (IFN) regulatory factor (IRF)3 by either lipopolysaccharide (LPS) or palmitic acid, resulting in suppression of IFN-β expression, but not that of NF-B or JNK. Moreover, statins strongly downregulated TLR3-mediated gene expressions by poly(I:C), but not TLR2-stimulation by zymosan A. Neutralization of IFN-β attenuated proinflammatory activities of the macrophage supernatant.

Conclusions— Statins partially attenuated the development of adipose tissue inflammation in obese mice, which might be associated with an inhibitory effect of statins on TLR4-triggered expression of IFN-β via MyD88-independent signaling pathway in macrophages.

We investigated the effects of HMG CoA reductase inhibitors (statins) on adipose tissue inflammation and macrophages. We found that treatment of obese mice with statins partially attenuated the development of adipose tissue inflammation, and that statins had an inhibitory effect on MyD88-independent IRF3/IFN-β pathway in macrophages.

Key Words: statin • macrophage • adipocyte • inflammation • IFN-β

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