Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Yasuyuki Kihara, Takuya Matsushita, Yoshihiro Kita, Satoshi Uematsu, Shizuo Akira, Jun-Ichi Kira, Satoshi Ishii, Takao Shimizu

研究成果: ジャーナルへの寄稿記事

86 引用 (Scopus)

抄録

The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using anAAcascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD2) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE2 pathway is favored and the PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1-/- mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-γ than mPGES-1 +/+ mice. Expression of PGE2 receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE2-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.

元の言語英語
ページ(範囲)21807-21812
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
106
発行部数51
DOI
出版物ステータス出版済み - 12 22 2009

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Autoimmune Experimental Encephalomyelitis
Prostaglandins E
Multiple Sclerosis
Arachidonic Acid
Prostaglandin D2
Eicosanoids
Therapeutics
Prostaglandin E Receptors
Arachidonate 5-Lipoxygenase
Cyclooxygenase 1
Interleukin-17
Microglia
Epoprostenol
Cyclooxygenase 2
Dinoprostone
Ulcer
Prostaglandins
Prostaglandin-E Synthases
Spinal Cord
Anti-Inflammatory Agents

All Science Journal Classification (ASJC) codes

  • General

これを引用

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. / Kihara, Yasuyuki; Matsushita, Takuya; Kita, Yoshihiro; Uematsu, Satoshi; Akira, Shizuo; Kira, Jun-Ichi; Ishii, Satoshi; Shimizu, Takao.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 106, 番号 51, 22.12.2009, p. 21807-21812.

研究成果: ジャーナルへの寄稿記事

Kihara, Yasuyuki ; Matsushita, Takuya ; Kita, Yoshihiro ; Uematsu, Satoshi ; Akira, Shizuo ; Kira, Jun-Ichi ; Ishii, Satoshi ; Shimizu, Takao. / Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. :: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; 巻 106, 番号 51. pp. 21807-21812.
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abstract = "The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using anAAcascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD2) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE2 pathway is favored and the PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1-/- mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-γ than mPGES-1 +/+ mice. Expression of PGE2 receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE2-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.",
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