Effects of statins on adipose tissue inflammation: their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages.
OBJECTIVE
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.


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-beta expression, but not that of NF-kappaB or JNK. Moreover, statins strongly downregulated TLR3-mediated gene expressions by poly(I:C), but not TLR2-stimulation by zymosan A. Neutralization of IFN-beta 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-beta via MyD88-independent signaling pathway in macrophages.
Abe
Manabu
M
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Matsuda
Morihiro
M
Kobayashi
Hironori
H
Miyata
Yugo
Y
Nakayama
Yuki
Y
Komuro
Ryutaro
R
Fukuhara
Atsunori
A
Shimomura
Iichiro
I
D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050838:Interferon Regulatory Factor-3 / Q000187:drug effects / Q000378:metabolism*; D016899:Interferon-beta / Q000187:drug effects / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D053594:Myeloid Differentiation Factor 88 / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D017035:Pravastatin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050838:Interferon Regulatory Factor-3; D015850:Interleukin-6; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011804:Quinolines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D017035:Pravastatin; C108475:pitavastatin