Pitavastatin Regulates Helper T-Cell Differentiation and Ameliorates Autoimmune Myocarditis in Mice View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-05-31

AUTHORS

Kazuko Tajiri, Nobutake Shimojo, Satoshi Sakai, Tomoko Machino-Ohtsuka, Kyoko Imanaka-Yoshida, Michiaki Hiroe, Yusuke Tsujimura, Taizo Kimura, Akira Sato, Yasuhiro Yasutomi, Kazutaka Aonuma

ABSTRACT

PurposeExperimental autoimmune myocarditis (EAM) is a mouse model of inflammatory cardiomyopathy, and the involvement of T helper (Th) 1 and Th17 cytokines has been demonstrated. Accumulated evidence has shown that statins have anti-inflammatory and immunomodulatory effects; however, the mechanism has not been fully elucidated. This study was designed to test the hypothesis that pitavastatin affects T cell-mediated autoimmunity through inhibiting Th1 and Th17 responses and reduces the severity of EAM in mice.MethodsThe EAM model was established in BALB/c mice by immunization with murine α-myosin heavy chain. Mice were fed pitavastatin (5 mg/kg) or vehicle once daily for 3 weeks from day 0 to day 21 after immunization.ResultsPitavastatin reduced the pathophysiological severity of the myocarditis. Pitavastatin treatment inhibited the phosphorylation of signal transducer and activator of transcription (STAT)3 and STAT4, which have key roles in the Th1 and Th17 lineage commitment, respectively, in the heart, and suppressed production of Th1 cytokine interferon-γ and Th17 cytokine interleukin-17 from autoreactive CD4+ T cells. In in vitro T-cell differentiation experiments, pitavastatin-treated T cells failed to differentiate into Th1 and Th17 cells through inhibiting the transcription of T-box expressed in T-cells (T-bet) and RAR-related orphan receptor γt (RORγT) which have critical roles in the development of Th1 and Th17 cells, respectively, and this failure was rescued by adding mevalonate.ConclusionsPitavastatin inhibits Th1 and Th17 responses and ameliorates EAM. These results suggest that statins may be a promising novel therapeutic strategy for the clinical treatment of myocarditis and inflammatory cardiomyopathy. More... »

PAGES

413-424

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10557-013-6464-y

DOI

http://dx.doi.org/10.1007/s10557-013-6464-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1032465056

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23722419


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29 schema:description PurposeExperimental autoimmune myocarditis (EAM) is a mouse model of inflammatory cardiomyopathy, and the involvement of T helper (Th) 1 and Th17 cytokines has been demonstrated. Accumulated evidence has shown that statins have anti-inflammatory and immunomodulatory effects; however, the mechanism has not been fully elucidated. This study was designed to test the hypothesis that pitavastatin affects T cell-mediated autoimmunity through inhibiting Th1 and Th17 responses and reduces the severity of EAM in mice.MethodsThe EAM model was established in BALB/c mice by immunization with murine α-myosin heavy chain. Mice were fed pitavastatin (5 mg/kg) or vehicle once daily for 3 weeks from day 0 to day 21 after immunization.ResultsPitavastatin reduced the pathophysiological severity of the myocarditis. Pitavastatin treatment inhibited the phosphorylation of signal transducer and activator of transcription (STAT)3 and STAT4, which have key roles in the Th1 and Th17 lineage commitment, respectively, in the heart, and suppressed production of Th1 cytokine interferon-γ and Th17 cytokine interleukin-17 from autoreactive CD4+ T cells. In in vitro T-cell differentiation experiments, pitavastatin-treated T cells failed to differentiate into Th1 and Th17 cells through inhibiting the transcription of T-box expressed in T-cells (T-bet) and RAR-related orphan receptor γt (RORγT) which have critical roles in the development of Th1 and Th17 cells, respectively, and this failure was rescued by adding mevalonate.ConclusionsPitavastatin inhibits Th1 and Th17 responses and ameliorates EAM. These results suggest that statins may be a promising novel therapeutic strategy for the clinical treatment of myocarditis and inflammatory cardiomyopathy.
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36 schema:keywords Accumulated evidence
37 Ameliorates Autoimmune Myocarditis
38 BALB/c mice
39 CD4
40 ConclusionsPitavastatin
41 EAM
42 EAM model
43 MethodsThe EAM model
44 PurposeExperimental autoimmune myocarditis
45 RAR
46 ResultsPitavastatin
47 STAT4
48 Th1
49 Th1 cytokine interferon
50 Th17 cells
51 Th17 cytokines
52 Th17 lineage commitment
53 Th17 responses
54 activator
55 activator of transcription
56 autoimmune myocarditis
57 autoimmunity
58 autoreactive CD4
59 box
60 c mice
61 cardiomyopathy
62 cell differentiation
63 cell differentiation experiments
64 cell-mediated autoimmunity
65 cells
66 chain
67 clinical treatment
68 commitment
69 critical role
70 cytokine interferon
71 cytokines
72 day 0
73 day 21
74 development
75 development of Th1
76 differentiation
77 differentiation experiments
78 effect
79 evidence
80 experiments
81 failure
82 fed pitavastatin
83 heart
84 heavy chain
85 helper 1
86 helper T
87 hypothesis
88 immunization
89 immunomodulatory effects
90 inflammatory cardiomyopathy
91 interferon
92 involvement
93 key role
94 lineage commitment
95 mechanism
96 mevalonate
97 mice
98 model
99 mouse model
100 murine α
101 myocarditis
102 myosin heavy chain
103 novel therapeutic strategies
104 orphan receptor γt
105 pathophysiological severity
106 phosphorylation
107 pitavastatin
108 pitavastatin treatment
109 production
110 promising novel therapeutic strategy
111 receptor γt
112 response
113 results
114 role
115 severity
116 severity of EAM
117 signal transducer
118 statins
119 strategies
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122 transcription
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