title: Effects of statins on adipose tissue inflammation: their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages.
abstract: 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.
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.forename: Morihiro
authors.initials: M
authors.lastname: Matsuda
authors.forename: Hironori
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Yugo
authors.initials: Y
authors.lastname: Miyata
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Komuro
authors.forename: Atsunori
authors.initials: A
authors.lastname: Fukuhara
authors.forename: Iichiro
authors.initials: I
authors.lastname: Shimomura
mesh_terms: 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
chemical_list: 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