Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production

Hideki Amuro, Tomoki Ito, Rie Miyamoto, Hiroyuki Sugimoto, Yoshitaro Torii, Yonsu Son, Naoto Nakamichi, Chihiro Yamazaki, Katsuaki Hoshino, Tsuneyasu Kaisho, Yoshio Ozaki, Muneo Inaba, Ryuichi Amakawa, Shirou Fukuhara

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Objective. Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. Methods. We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNα production, and intracellular signaling. Results. Statins inhibited IFNα production profoundly and tumor necrosis factor α production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNα production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNα production by PDCs from SLE patients and SLE serum-induced IFNα production. Conclusion. Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.

Original languageEnglish
Pages (from-to)2073-2085
Number of pages13
JournalArthritis and Rheumatism
Volume62
Issue number7
DOIs
Publication statusPublished - Jul 2010
Externally publishedYes

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Interferon Type I
Interferons
Oxidoreductases
Dendritic Cells
Systemic Lupus Erythematosus
Autoimmune Diseases
Interferon Regulatory Factor-7
3-hydroxy-3-methylglutaryl-coenzyme A
rho-Associated Kinases
Simvastatin
Toll-Like Receptors
p38 Mitogen-Activated Protein Kinases
Transferases
Flow Cytometry
Tumor Necrosis Factor-alpha
Cholesterol
Ligands

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production. / Amuro, Hideki; Ito, Tomoki; Miyamoto, Rie; Sugimoto, Hiroyuki; Torii, Yoshitaro; Son, Yonsu; Nakamichi, Naoto; Yamazaki, Chihiro; Hoshino, Katsuaki; Kaisho, Tsuneyasu; Ozaki, Yoshio; Inaba, Muneo; Amakawa, Ryuichi; Fukuhara, Shirou.

In: Arthritis and Rheumatism, Vol. 62, No. 7, 07.2010, p. 2073-2085.

Research output: Contribution to journalArticle

Amuro, H, Ito, T, Miyamoto, R, Sugimoto, H, Torii, Y, Son, Y, Nakamichi, N, Yamazaki, C, Hoshino, K, Kaisho, T, Ozaki, Y, Inaba, M, Amakawa, R & Fukuhara, S 2010, 'Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production', Arthritis and Rheumatism, vol. 62, no. 7, pp. 2073-2085. https://doi.org/10.1002/art.27478
Amuro, Hideki ; Ito, Tomoki ; Miyamoto, Rie ; Sugimoto, Hiroyuki ; Torii, Yoshitaro ; Son, Yonsu ; Nakamichi, Naoto ; Yamazaki, Chihiro ; Hoshino, Katsuaki ; Kaisho, Tsuneyasu ; Ozaki, Yoshio ; Inaba, Muneo ; Amakawa, Ryuichi ; Fukuhara, Shirou. / Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production. In: Arthritis and Rheumatism. 2010 ; Vol. 62, No. 7. pp. 2073-2085.
@article{905dd7ab79cf4a259925ced7744c0484,
title = "Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production",
abstract = "Objective. Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. Methods. We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNα production, and intracellular signaling. Results. Statins inhibited IFNα production profoundly and tumor necrosis factor α production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNα production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNα production by PDCs from SLE patients and SLE serum-induced IFNα production. Conclusion. Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.",
author = "Hideki Amuro and Tomoki Ito and Rie Miyamoto and Hiroyuki Sugimoto and Yoshitaro Torii and Yonsu Son and Naoto Nakamichi and Chihiro Yamazaki and Katsuaki Hoshino and Tsuneyasu Kaisho and Yoshio Ozaki and Muneo Inaba and Ryuichi Amakawa and Shirou Fukuhara",
year = "2010",
month = "7",
doi = "10.1002/art.27478",
language = "English",
volume = "62",
pages = "2073--2085",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "7",

}

TY - JOUR

T1 - Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production

AU - Amuro, Hideki

AU - Ito, Tomoki

AU - Miyamoto, Rie

AU - Sugimoto, Hiroyuki

AU - Torii, Yoshitaro

AU - Son, Yonsu

AU - Nakamichi, Naoto

AU - Yamazaki, Chihiro

AU - Hoshino, Katsuaki

AU - Kaisho, Tsuneyasu

AU - Ozaki, Yoshio

AU - Inaba, Muneo

AU - Amakawa, Ryuichi

AU - Fukuhara, Shirou

PY - 2010/7

Y1 - 2010/7

N2 - Objective. Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. Methods. We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNα production, and intracellular signaling. Results. Statins inhibited IFNα production profoundly and tumor necrosis factor α production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNα production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNα production by PDCs from SLE patients and SLE serum-induced IFNα production. Conclusion. Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.

AB - Objective. Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. Methods. We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNα production, and intracellular signaling. Results. Statins inhibited IFNα production profoundly and tumor necrosis factor α production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNα production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNα production by PDCs from SLE patients and SLE serum-induced IFNα production. Conclusion. Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.

UR - http://www.scopus.com/inward/record.url?scp=77954240134&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954240134&partnerID=8YFLogxK

U2 - 10.1002/art.27478

DO - 10.1002/art.27478

M3 - Article

C2 - 20506142

AN - SCOPUS:77954240134

VL - 62

SP - 2073

EP - 2085

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 7

ER -