title: Statins decrease lung inflammation in mice by upregulating tetraspanin CD9 in macrophages.
abstract: Tetraspanins organize protein complexes in tetraspanin-enriched membrane microdomains that are distinct from lipid rafts. Our previous studies suggested that reduction in the levels of tetraspanins CD9 and CD81 may be involved in the progression of inflammatory lung diseases, especially COPD. To search for agents that increase the levels of these tetraspanins, we screened 1,165 drugs in clinical use and found that statins upregulate CD9 and CD81 in RAW264.7 macrophages. The lipophilic statins, fluvastatin and simvastatin, reversed LPS-induced downregulation of CD9 and CD81, simultaneously preventing TNF-α and matrix metalloproteinase-9 production and spreading of RAW264.7 cells. These statins exerted anti-inflammatory effects in vitro in wild-type macrophages but not in CD9 knockout macrophages, and decreased lung inflammation in vivo in wild-type mice but not in CD9 knockout mice, suggesting that their effects are dependent on CD9. Mechanistically, the statins promoted reverse transfer of the LPS-signaling mediator CD14 from lipid rafts into CD9-enriched microdomains, thereby preventing LPS receptor formation. Finally, upregulation of CD9/CD81 by statins was related to blockade of GTPase geranylgeranylation in the mevalonate pathway. Our data underscore the importance of the negative regulator CD9 in lung inflammation, and suggest that statins exert anti-inflammatory effects by upregulating tetraspanin CD9 in macrophages.
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yingji
authors.initials: Y
authors.lastname: Jin
authors.forename: Isao
authors.initials: I
authors.lastname: Tachibana
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takeda
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.forename: Mayumi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hanako
authors.initials: H
authors.lastname: Kuhara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tetsumoto
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsujino
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Minami
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Kaori
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kohmo
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Hirata
authors.forename: Ryo
authors.initials: R
authors.lastname: Takahashi
authors.forename: Koji
authors.initials: K
authors.lastname: Inoue
authors.forename: Izumi
authors.initials: I
authors.lastname: Nagatomo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.forename: Takashi
authors.initials: T
authors.lastname: Kijima
authors.forename: Mari
authors.initials: M
authors.lastname: Ito
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D021381:Protein Transport / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology; D060225:Tetraspanin 28 / Q000235:genetics / Q000378:metabolism; D060245:Tetraspanin 29 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D014409:Tumor Necrosis Factor-alpha; D000077340:Fluvastatin; D019821:Simvastatin; D020780:Matrix Metalloproteinase 9
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