Attenuation of experimental autoimmune myocarditis by blocking T cell activation through 4-1BB pathway

Haga, Takaaki; Suzuki, Jun–ichi; Kosuge, Hisanori; Ogawa, Masahito; Saiki, Hitoshi; Haraguchi, Go; Maejima, Yasuhiro; Isobe, Mitsuaki; Uede, Toshimitsu

doi:10.1016/j.yjmcc.2009.02.003

Cited by 31 publications

(36 citation statements)

References 31 publications

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“…Additionally, IVSTd value was reduced in the EAM ϩ IKKi (14 -20) group compared with that of the EAM ϩ vehicle group, although LVPWd value was not changed. There was no significant difference regarding IVSTd and LVPWd values between the EAM ϩ IKKi (14)(15)(16)(17)(18)(19)(20) group and the EAM ϩ IKKi(1-20) group (Table 1 and Fig. 1).…”

Section: Echocardiographic Parametersmentioning

confidence: 86%

“…The severity of histological myocardial damage characterized by cell infiltration and fibrosis was significantly reduced in both the EAM ϩ IKKi (14 -20) group and the EAM ϩ IKKi(1-20) group compared with the EAM ϩ vehicle group. Additionally, it should be noted that there was no significant difference regarding this effect between the EAM ϩ IKKi(14 -20) group and the EAM ϩ IKKi (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) (14 -20)] was a trial to inspect utility as a therapeutic medicine of myocarditis. Meanwhile, there was no significant difference in echocardiographic parameters and histopathological findings between the normal ϩ vehicle group and the normal ϩ IKKi(1-20) group.…”

Section: Discussionmentioning

confidence: 99%

“…Although acute myocardial inflammation is an essential etiology for its progression, no effective treatment has been elucidated (3,13,30,49). Because autoimmunity is important in myocarditis, a reaction to cardiac myosin may contribute to the development (14). In the pathology of myocarditis, T cells activated by antigen infiltrate into the myocardium, which may lead to myocardial damage by inflammatory reaction to myosin (23).…”

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confidence: 99%

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Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation

Watanabe

Azuma

Suzuki

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg(-1)·day(-1)) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.

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Section: Echocardiographic Parametersmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation

Watanabe

Azuma

Suzuki

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recent studies suggest that CD137-CD137 ligand (CD137L) interactions may participate in multiple stages of inflammation (16)(17)(18)(19)(20)(21)(22). During antigen presentation and T-cell proliferation, CD137L on antigen-presenting cells (APCs) can costimulate CD137 on Th1 helper T cells, acting as a master regulator for the classical inflammatory pathway.…”

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confidence: 99%

Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation

Kim¹,

Lee

Kim³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell-TECneutrophil axis, whereby CD137-CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.acute inflammation | costimulatory ligand

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“…Rats were injected subcutaneously in the rear foot pads with this emulsion on days 0 and 7. 24,25) Rats were also injected intravenously with either PBS alone, control small hairpin siRNA vector expressing a scrambled siRNA (negative control siR-NA), or small hairpin CD40 siRNA-expressing vector (CD40 siRNA) on day 7 after the second myosin injection. Histology: Upon sacrifice, the rat hearts were immediately removed and weighed, and the ratios of heart weight/body weight (g/kg) were then calculated.…”

Section: Methodsmentioning

confidence: 99%

Attenuation of Experimental Autoimmune Myocarditis by si-RNA Mediated CD40 Silencing

Gong

Han

Zou³

et al. 2014

Int. Heart J.

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SummaryCD40 plays an important role in the pathogenesis of myocarditis, and inhibition of CD40 expression could be a promising treatment for myocarditis. In this study, we used an animal model, experimental autoimmune myocarditis (EAM), to investigate whether CD40 siRNA could be exploited for myocarditis therapy.Lewis rats were immunized with purified porcine cardiac myosin to induce EAM or were injected with phosphatebuffered saline (PBS) alone (PBS group), scrambled small interfering RNA (siRNA) (negative control group), or CD40-siRNA (CD40 siRNA group).CD40 siRNA treatment suppressed the increase in heart weight/body weight ratio, and attenuated the severity of myocardial lesions. Cytokine production, including Th1-type cytokines, was significantly suppressed in rats with myocarditis after CD40 siRNA treatment; however, production of Th2-type cytokines was higher. Specific knockdown of CD40 in EAM rats resulted in increased FOXP3 gene expression and the CD25+ CD4+ subpopulation of T cells but also a decrease in CD80 and CD86 expression. Lymphocyte (T and B cell) proliferation in response to myosin stimulation was significantly inhibited by CD40 silencing.CD40-siRNA is a useful tool for inhibiting in vivo CD40 expression, and it could have therapeutic potential in the prevention and treatment of myocarditis in humans. (Int Heart J 2014; 55: 539-545) Key words: RNA interference, Lymphocyte M yocarditis, an inflammatory heart muscle disease associated with cardiac dysfunction, can be caused by many agents, such as viruses and drugs, and is a potentially lethal disease, which can cause sudden death. 1,2)The disease has acute and chronic phases. Patients with myocarditis may develop dilated cardiomyopathy, which represents the chronic phase of the disease that leads to heart failure. 3)While there is still no effective therapy for myocarditis, recent studies have shown that autoimmunity plays an important role in the pathogenesis and development of myocarditis. 4) Experimental autoimmune myocarditis (EAM) is a model of post-infectious myocarditis, and can be induced by severe myocardial damage, including infiltration of mononuclear cells into the myocardium and activation of dendritic cells (DCs), with the subsequent activation of autoreactive T-cells, along with the secreted cytokines. 5-7)RNA interference is a post-transcriptional mechanism of gene silencing in which siRNA can lead to specific endonucleolytic cleavage of mRNA.8) RNA interference with siRNA is a specific, long-lasting, and straightforward approach for blocking the expression of specific genes.9) The therapeutic use of siRNA is promising, due to sequence-specific gene silencing, and has been successfully used in several animal models of diseases and clinical trials. 10)CD40 is a member of the TNF receptor superfamily and, as a co-stimulatory molecule, it plays critical roles in T cell activation and differentiation.11,12) CD40 expression can stimulate Th1 activation, 13,14) and the CD40/CD40 ligand (CD40L) interaction has been demonstrated to e...

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Attenuation of experimental autoimmune myocarditis by blocking T cell activation through 4-1BB pathway

Cited by 31 publications

References 31 publications

Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation

Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation

Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation

Attenuation of Experimental Autoimmune Myocarditis by si-RNA Mediated CD40 Silencing

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